* 134797

FIBRILLIN 1; FBN1


Alternative titles; symbols

FIBRILLIN; FBN


HGNC Approved Gene Symbol: FBN1

Cytogenetic location: 15q21.1     Genomic coordinates (GRCh38): 15:48,408,313-48,645,709 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
15q21.1 Acromicric dysplasia 102370 AD 3
Ectopia lentis, familial 129600 AD 3
Geleophysic dysplasia 2 614185 AD 3
Marfan lipodystrophy syndrome 616914 AD 3
Marfan syndrome 154700 AD 3
MASS syndrome 604308 AD 3
Stiff skin syndrome 184900 AD 3
Weill-Marchesani syndrome 2, dominant 608328 AD 3

TEXT

Description

Fibrillin is the major constitutive element of extracellular microfibrils and has widespread distribution in both elastic and nonelastic connective tissue throughout the body. The cDNA was identified in 1991 and was mapped coincident with the locus for Marfan syndrome. Subsequent studies confirmed that mutations in the FBN1 gene are the major cause of Marfan syndrome (MFS; 154700).


Cloning and Expression

The connective tissue protein fibrillin was isolated from the medium of human fibroblast cell cultures and was characterized and named by Sakai et al. (1986). Using monoclonal antibodies specific for fibrillin, they demonstrated its widespread distribution in the connective tissue matrices of skin, lung, kidney, vasculature, cartilage, tendon, muscle, cornea, and ciliary zonule. The molecular weight of fibrillin is about 350,000 Da. Sakai et al. (1991) pointed out that fibrillin contains approximately 14% cysteine, of which one-third appears to be in the free reactive sulfhydryl form.

Maslen et al. (1991) isolated cDNA clones for the fibrillin gene. Corson et al. (1993) and Pereira et al. (1993) completed characterization of the fibrillin cDNA, elucidated the exon/intron organization of the gene, and derived a physical map of the locus. The profibrillin sequence encodes a 2,871-amino acid protein which, excluding the signal peptide, is arranged into 5 structurally distinct regions. The largest of these regions, comprising about 75% of the protein, are the 46 EGF-like repeats, cysteine-rich domains originally found in human epidermal growth factor (131530). Forty-three of these repeats satisfy the consensus for calcium binding, an event that may mediate protein-protein interactions, and are called calcium-binding EGF-like repeats (cbEGFs). A mutation in one of these EGF-like repeats was identified in a Marfan syndrome patient; see 134797.0001. The tandem repetition of EGF-like domains is interrupted by 8 cysteine motifs that have homology to a domain first recognized in transforming growth factor beta-1-binding protein (TGFBR1; 190181), called a TB domain. Almost all of the EGF-like repeats are encoded by single exons. The other 4 regions include a unique amino-terminal stretch of basic residues, an adjacent second cysteine-rich region, a proline-rich domain, and the carboxy terminus.

Using immunohistochemical analysis, Quondamatteo et al. (2002) investigated the distribution of fibrillin 1 and fibrillin 2 (FBN2; 612570) in human embryonic and early fetal tissues between gestational weeks 5 and 12. Both fibrillins were widely distributed. In most embryonic and early fetal organs, such as skin, lung, heart, aorta, central nervous system anlage, nerves, and ganglia, both fibrillins followed the same temporospatial pattern of distribution. However, in kidney, liver, rib anlagen, and notochord, distribution of FIB1 and FIB2 differed.


Gene Structure

The fibrillin gene is relatively large, and the coding sequence is divided into 65 exons (Corson et al., 1993; Pereira et al., 1993). Corson et al. (1993) described 3 alternatively spliced exons at the 5-prime end, which they termed exon B, exon A, and exon C. A CpG island was identified that spans the first 2 alternatively spliced exons.

Biery et al. (1999) estimated the size of the FBN1 gene to be 200 kb.


Mapping

Upon identification of intragenic polymorphisms within the FBN1 gene, Dietz et al. (1991) and Lee et al. (1991) demonstrated linkage between the FBN1 locus and the previously mapped Marfan syndrome locus at 15q15-q21.1. Using clones derived from fibrillin cDNA as probes in isotopic and nonisotopic in situ hybridization studies, Magenis et al. (1991) mapped the human fibrillin gene to 15q21.1.

Velinov et al. (1993) demonstrated linkage between the FBN1 locus and the locus for limb-girdle muscular dystrophy (LGMD2A; 253600), which had previously been mapped to 15q15.1-q21.1. In a large Amish kindred segregating LGMD, they found a maximum lod score of 9.135 at theta = 0.04.

By analysis of a mapping panel of mouse/hamster somatic hybrid cell lines, Li et al. (1993) demonstrated that the murine homolog of the FBN1 gene is located on chromosome 2.


Gene Function

Corson et al. (1993) demonstrated that fibrillin molecules bind calcium.

Using in situ hybridization and immunohistochemical analysis, Zhang et al. (1995) showed that Fib1 and Fib2 were differentially expressed in a temporal and spatial manner during mouse and rat development. In the majority of cases, Fib2 transcripts appeared earlier and accumulated for a shorter period of time than Fib1 transcripts. Synthesis of Fib1 correlated with late morphogenesis and the appearance of well-defined organ structures. Conversely, Fib2 synthesis coincided with early morphogenesis and the beginning of elastogenesis. Zhang et al. (1995) proposed that FIB1 provides mostly force-bearing structural support, whereas FIB2 predominantly regulates the early process of elastic fiber assembly.

Trask et al. (1999) found that human FIB1 and FIB2 homodimerized via an N-terminal region and that the interaction was stabilized by disulfide bonds. Dimer formation occurred intracellularly, suggesting that the process of fibrillin aggregation initiates early after biosynthesis of the molecules. No heterodimers of FIB1 and FIB2 were observed, suggesting that the pro- and gly-rich domains of FIB1 and FIB2, respectively, determine the specificity of dimer formation.

Lin et al. (2002) showed that the N terminus of human FIB1 could assemble in a linear fashion with the C terminus of another FIB1 molecule to form homotypic FIB1 microfibrils in the presence of calcium. FIB1 could interact similarly with FIB2 to form heterotypic microfibrils, but FIB2 N- and C-terminal constructs showed no significant interaction with one another. In dermal fibroblasts from a 1-year-old donor, both FIB1 and FIB2 were detected in a microfibrillar network. In contrast, osteoblasts from a 42-year-old donor showed a microfibrillar network made up of FIB1 alone. Lin et al. (2002) concluded that FIB1 can form microfibrillar structures in the absence of FIB2, and that FIB2 can occur in microfibrils with FIB1.

Using immunohistochemical analysis and immunogold microscopy of embryonic and adult mouse, Tsutsui et al. (2010) found that Adamtsl6 (THSD4; 614476) colocalized with fibrillin-1 in fibrillar structures of various elastic tissues. The recombinant Adamtsl6-beta isoform interacted with the N-terminal half of fibrillin-1 in a dose-dependent manner. When transfected into human osteosarcoma cells, both Adamtsl6 isoforms promoted formation of fibrillin-1 microfibrils in a dose-dependent manner that was independent of fibrillin-1 synthesis. Fibrillin-1 deposition in the extracellular matrix was enhanced in transgenic mice overexpressing Adamtsl6-beta in cartilaginous tissues. Tsutsui et al. (2010) concluded that ADAMTSL6 promotes the assembly of fibrillin-1 microfibrils.

Duerrschmid et al. (2017) noted that Romere et al. (2016) had shown that obesity in humans and mice is associated with a pathologic increase in the C-terminal cleavage product of profibrillin, asprosin. To ascertain whether asprosin stimulates appetite, Duerrschmid et al. (2017) administered recombinant asprosin subcutaneously to wildtype mice, and observed greater food intake over the next 24 hours. Daily subcutaneous injections of asprosin resulted in hyperphagia and a significant increase in adiposity. Adenovirus-mediated overexpression of human FBN1 resulted in an approximately 2-fold increase in plasma asprosin and a similar hyperphagic response; the increase in adiposity was potentiated when the mice were given a high-fat diet. The authors observed that exposure to recombinant asprosin acutely induced activation of known orexigenic AgRP+ neurons within the hypothalamus by increasing the firing frequency as well as the resting membrane potential. Ablation of AgRP+ neurons completely eliminated asprosin's orexigenic drive in mice on normal chow. However, when exposed to a high-fat diet, the ablated mice responded to asprosin, suggesting that a highly palatable diet is able to engage neuronal populations differently from those involved in normal hunger signals. Experiments with hypothalamic cells exposed to various inhibitors revealed that asprosin directly activates orexigenic AgRP+ neurons via a cAMP-dependent pathway. Duerrschmid et al. (2017) showed that this signaling causes inhibition of downstream anorexigenic proopiomelanocortin (POMC; 176830)-positive neurons in a GABA-dependent manner, which results in appetite stimulation and a drive to accumulate adiposity and body weight.


Molecular Genetics

Marfan Syndrome

Data from several studies suggested fibrillin as a possible candidate gene for Marfan syndrome (154700). Fibrillin was immunolocalized to the ciliary zonule (Sakai et al., 1986), a ligamentous structure consisting mainly of fibrillin microfibrils which is characteristically affected in the Marfan syndrome. Hollister et al. (1990) demonstrated abnormal immunohistochemical patterns in the skin and cultured fibroblasts of patients with the Marfan syndrome. By pulse-chase analysis, Milewicz et al. (1992) demonstrated reproducible patterns of abnormal fibrillin-1 synthesis, secretion, or extracellular matrix utilization in the vast majority of fibroblast cell cultures from Marfan syndrome patients. Furthermore, the Marfan phenotype had been mapped by linkage studies to the same region of chromosome 15 that contained the fibrillin gene. The demonstration of linkage between the fibrillin gene (as recognized by a TaqI restriction site polymorphism) and the Marfan phenotype, combined with the demonstration of point mutations within the fibrillin gene in patients with classic Marfan syndrome (Dietz et al., 1991), concluded the proof that FBN1 is 'the Marfan gene.' In a letter received February 4, 1992, Hayward et al. (1992) stated that of the 2 fibrillin mutations discovered up to that time, arg239-to-pro (now designated as codon 1137; 134797.0001) had been found twice in 111 cases and cys1409-to-ser (now designated as codon 2307; 134797.0002) had been found once in 140 cases (mutations being scored once for each sporadic case and once for each family segregating the gene). They concluded that there are likely to be many different FBN1 mutations responsible for the Marfan syndrome.

Dietz et al. (1992) pointed out that all 5 missense mutations characterized to that time occurred within the EGF-like repeats of the FBN1 gene. In addition, 4 of the 5 involved the substitution of cysteine residues, and 3 of the 5 substituted the third cysteine in the EGF-like motif consensus sequence.

By screening 44 probands with Marfan syndrome or related phenotypes for alterations in the entire fibrillin coding sequence of 9.3 kb by single-strand conformation analysis, Tynan et al. (1993) found 4 unique mutations in unrelated patients. One was a 17-bp deletion and 3 were missense mutations, 2 of which involved 8-cysteine motifs. Another missense mutation was found in 2 unrelated patients with annuloaortic ectasia but was present in unaffected relatives and controls from various ethnic backgrounds. Their results suggested that most Marfan syndrome families carry unique mutations; the original arg1137-to-pro mutation, found twice in a pool of 43 patients by Dietz et al. (1991), remained the only example of a mutation described in more than 1 family.

Dietz et al. (1993) described 4 novel FBN1 mutations by screening the FBN1 gene, including the 5-prime coding sequence. Two of them were missense mutations that, like all of the previously identified ones, were associated with classic and moderate to severe disease and occurred at residues with putative significance for calcium binding to EGF-like domains. In contrast, the 2 novel mutations that created premature signals for termination of translation of mRNA were associated with reduction in the amount of mutant allele transcript and produced a range of phenotypic severity. The patient with the lowest amount of mutant transcript had an extremely mild phenotype that did not satisfy the diagnostic criteria for Marfan syndrome. The data were interpreted as supporting a role for altered calcium binding to EGF-like domains in the pathogenesis of Marfan syndrome and suggested a dominant-negative mechanism for the pathogenesis of this disorder.

Using pulse-chase studies with (35)S-cysteine-labeled fibrillin on fibroblast strains from 55 patients with Marfan syndrome, Aoyama et al. (1994) found that the quantitation of the soluble intracellular and insoluble extracellular fibrillin allowed discrimination of 5 groups. Groups I and II synthesized reduced amounts of normal-sized fibrillin, while synthesis was normal in groups III, IV, and V. When extracellular fibrillin deposition was measured, groups I and III deposited between 35 and 70% of control values, groups II and IV less than 35%, and group V more than 70%. A deletion mutant with a low transcript level from the mutant allele and 7 additional patients had the group I protein phenotype. Disease in these patients is proposed to be caused by a reduction in microfibrils associated with either a null allele, an unstable transcript, or an altered fibrillin product synthesized in low amounts. In 68% of the Marfan syndrome individuals (groups II and IV), a dominant-negative effect was invoked as the main pathogenetic mechanism. Aoyama et al. (1994) proposed that products made by the mutant allele in these fibroblasts interfered with microfibril formation. Seven of the 9 known missense mutations, giving rise to abnormal but normal-sized fibrillin molecules, were in group IV. In 4 of the 55 fibroblast strains, no defect in fibrillin metabolism could be identified with the pulse-chase method. All 4 were sporadic cases and, therefore, linkage studies with polymorphic markers could not be checked to determine relationship to the FBN1 locus. One of the possibilities considered by Aoyama et al. (1994) was the involvement of some other protein that is associated with microfibrils, such as elastin (130160), thrombospondin (188062), microfibril-associated glycoprotein (156790), emilin (130660), or fibrillin-2 (121050).

Eldadah et al. (1995) addressed the question of whether Marfan syndrome results from a deficiency of wildtype fibrillin (haploinsufficiency), from a dominant-negative effect in which mutant fibrillin monomers disrupt the function of the wildtype protein encoded by the normal allele, or from a dynamic and variable interplay between these 2 pathogenetic mechanisms. To address this issue in a cell culture system, they stably transfected normal human and murine fibroblasts with a mutant fibrillin allele from a patient with severe Marfan syndrome. The mutation was a G-to-A transition at position +1 of the donor splice site of intron 2 that resulted in the skipping of exon 2, a frameshift, and a subsequent premature termination codon in exon 4. Immunohistochemical analysis of the resultant cell lines demonstrated markedly diminished fibrillin deposition and disorganized microfibrillar architecture. Pulse-chase studies showed normal levels of fibrillin synthesis but substantially reduced deposition into the extracellular matrix. These data illustrated that expression of a mutant fibrillin allele, on a background of 2 normal alleles, is sufficient to disrupt normal microfibrillar assembly and to reproduce the Marfan cellular phenotype. The findings in cell culture underscored the importance of the fibrillin amino-terminus in normal microfibrillar assembly and suggested that expression of the human extreme 5-prime fibrillin coding sequence may be sufficient, in isolation, to produce an animal model of the Marfan syndrome. Lastly, this substantiation of a dominant-negative effect offered mutant allele knockout as a potential strategy for gene therapy (see Dietz and Pyeritz, 1994).

In a 66-year-old female with Marfan syndrome, Hewett et al. (1994) found a heterozygous G-to-A mutation at nucleotide 3952 of the FBN1 gene, resulting in a C1223Y substitution within an EGF-like domain (134797.0022). Dietz et al. (1995) found the C1223Y mutation in the FBN1 gene in a patient with Marfan syndrome who also had features of Shprintzen-Goldberg syndrome (SGS; 182212), including craniosynostosis and mental retardation. Kosaki et al. (2006) also reported a patient who had features of both disorders and a mutation in the FBN1 gene (C1221Y; 134797.0045). It may be significant that both of these mutations reside in the same EGF-like domain of fibrillin (Doyle et al., 2012).

Among the many clinical applications of PCR is its potential use in preimplantation diagnosis of genetic disorders. Eldadah et al. (1995) discussed the use of PCR in the molecular detection of heterozygous genetic mutations. In principle, performing PCR on single blastomeres from early cleavage stage (6- to 8-cell) human embryos should enable reliable determination of disease status for certain inherited conditions. However, reports of misdiagnoses using this technique diminished enthusiasm for its widespread clinical use. A principal source of error is the propensity for genome-targeted PCR to amplify one allele exclusively in reactions assaying a single heterozygous diploid cell. Complete reaction failure is also common. Employing the Marfan syndrome as a paradigm, Eldadah et al. (1995) developed a reliable, RT-PCR-based method for genotyping single cells that overcomes these obstacles. The technique should facilitate accurate preimplantation diagnosis of Marfan syndrome and other selected genetic diseases caused by heterozygous or compound heterozygous mutations.

The large size of the FBN1 gene as well as other factors precluded routine mutation screening for presymptomatic and prenatal diagnosis. Judge et al. (2001) identified and localized highly polymorphic microsatellite markers that fall within 1 Mb of FBN1. Complete haplotype heterozygosity was observed in a population of 50 unrelated control individuals when the flanking markers and existing intragenic polymorphisms were used in combination. They demonstrated the usefulness of haplotype segregation analysis in the presymptomatic diagnosis and counseling of families showing atypical or equivocal manifestations of MFS.

Downing et al. (1996) described the nuclear magnetic resonance-derived structure of a covalently linked pair of calcium-binding epidermal growth factor-like domains from human fibrillin-1. The 2 domains are in a rigid, rod-like arrangement, stabilized by interdomain calcium-binding and hydrophobic interactions. They proposed a model for the arrangement of fibrillin monomers in microfibrils that reconciles structural and antibody binding data, and described a set of disease-causing mutations that provide the first clues to the specificity of the interactions of the calcium-binding EGF domains. The residues involved in stabilizing the domain linkage are highly conserved in fibrillin, fibulin (135820), thrombomodulin (188040), and the low density lipoprotein receptor (606945). They suggested that all reported mutations can be divided into 3 groups according to their effects on disulfide bond formation, calcium binding, and intra- and intermolecular interactions.

Liu et al. (1996) developed a simple and highly efficient long RT-PCR approach for rapid detection of exon-skipping mutations in FBN1. This approach led to the identification of 6 different exon skipping mutations, including 5 not previously reported and 1 recurring mutation. Liu et al. (1996) extracted total RNA from cultured fibroblasts from Marfan probands and the entire FBN1 cDNA was amplified in 3 overlapping fragments 3-4 kb in size. They compared the restriction patterns of long RT-PCR products amplified from normal and patient samples and identified 1 mutation in a 4 kb fragment which included exons 1-31, 2 mutations in fragments from exons 28-52, and 3 mutations in fragments spanning exons 47-65. DNA from the altered bands was gel purified, reamplified, and directly sequenced. In a panel of 60 Marfan probands Liu et al. (1996) identified 6 exon-skipping mutations. All skipped exons encoded calcium-binding epidermal growth factor (EGF)-like domains and maintained the reading frame. In 5 probands, exon skipping was due to point mutations in splice site sequences and in 1 case it was due to a 6-bp deletion in a donor splice site. Fibrillin synthesis and secretion was normal. Deposition of newly synthesized fibrillin into extracellular matrix was very much reduced. They carried out genotype/phenotype correlations and concluded that patients with in-frame skipping of an exon in their FBN transcripts tended to have a severe phenotype. Liu et al. (1996) demonstrated that the mutant mRNA missing an in-frame exon is stable and is only slightly shorter than normal fibrillin. They also demonstrated that both the normal and the abnormal forms are secreted and both forms of fibrillin molecules participate in the formation of microfibrils. Liu et al. (1996) concluded that the abnormal fibrillin forms therefore have a dominant-negative effect.

Although many of the mutation reports published prior to 1993 used a codon numbering system based upon a partial cDNA sequence, this entry uses the numbering system of Pereira et al. (1993) which reflects the characterization of the entire coding sequence for fibrillin.

Collod et al. (1996) described a software package and computerized database to facilitate search for mutations in the FBN1 gene. By the fall of 1995, 63 mutations in the FBN1 gene had been reported. These were almost entirely private, for the most part missense, nonrecurrent, and widely distributed throughout the gene. The mutations were presented in tabular form. The database was made available in Macintosh format on floppy disc. Collod-Beroud et al. (1997) described the second version of the computerized Marfan database, which contained 89 entries. The FBN1 gene has been found to harbor mutations related to a spectrum of conditions phenotypically related to MFS. These mutations are private, essentially missense, generally nonrecurrent, and widely distributed throughout the gene. To that time, no clear genotype/phenotype relationship had been observed except for the localization of neonatal mutations in a cluster between exons 24 and 32.

In 2 male patients with dilation of the aortic root, 1 of whom underwent acute dissection of the ascending thoracic aorta, Milewicz et al. (1996) identified 2 distinct heterozygous missense mutations in the FBN1 gene that were not found in 80 controls or 37 patients with thoracic aortic aneurysm. Both patients had high-arched palates and mitral valve prolapse, and both had undergone inguinal herniorrhaphies in their early 30s. One man had mild pectus excavatum and pes cavus with mild contractures of the toes, and the other had mild thoracic scoliosis.

Hayward et al. (1997) screened all 65 exons of the FBN1 gene in 20 Marfan syndrome families where at least 2 affected individuals were characterized and available for analysis, another 30 families with only 1 affected member available for analysis, and in 10 sporadic cases. In large well-characterized families with more than 4 affected individuals, the detection rate for mutations rose to 78% (7 of 9). In families where only 1 affected member was available, the mutation detection rate was 17% (5 of 30), and in sporadic cases it was 20% (2 of 10). In addition, they found 8 neutral polymorphisms. Twelve of the 17 disease-causing mutations had not been previously described, thus raising the total number of different FBN1 mutations reported to 85 in 94 unrelated cases. Both SSCP and heteroduplex analysis were used in the analyses of all 60 probands.

Hayward and Brock (1997) reviewed 97 different disease-associated single mutations in the FBN1 gene. Most of these mutations have been nonrecurring and, with the exception of the severe neonatal form of Marfan syndrome, spread throughout the gene with no obvious phenotypic association. Hayward and Brock (1997) stated that many cases of Marfan syndrome remain whose cause of abnormality is still undefined.

Montgomery et al. (1998) described molecular mechanisms underlying subdiagnostic variants of Marfan syndrome. In 1 family, an R1265C mutation (134797.0031) was found in mother and son with fully typical Marfan syndrome. Two other sons of the woman were said to be affected but haplotype and mutation analyses indicated that they could not have carried the mutation, despite the suggestive clinical findings. In a second family, multiple members were thought to have a nonspecific connective tissue disorder with dolichostenomelia, joint hypermobility, kyphoscoliosis, pes planus, positive wrist and thumb signs, striae distensae, early myopia, and myxomatous mitral leaflets with mitral valve prolapse. Because of the lack of dislocated lens or aortic dilatation, they were thought not to fulfill the diagnostic criteria for Marfan syndrome. However, an R1170H mutation was found in the FBN1 gene (134797.0032). In a third family, the proband had severe manifestations of Marfan syndrome, including aortic root dilatation to 8 cm, and was found to carry an R529X mutation in the FBN1 gene (134797.0033). The proband's mother, who was 60 years of age at the time of report, showed only joint hypermobility, pes planus, and striae distensae over the abdomen and trunk. There was no myopia or lens dislocation, and aortic measurements were within normal limits. The mother was found to be a mosaic for the R529X mutation.

The patients reported by Montgomery et al. (1998) were said to have subdiagnostic variants of the Marfan syndrome because they did not satisfy the diagnostic criteria proposed by De Paepe et al. (1996). According to these revised criteria, at least 1 of 4 manifestations with major diagnostic significance (lens dislocation, aortic dilatation or dissection, dural ectasia, or specific combinations of skeletal features) and involvement of at least one other system must be present for Marfan syndrome to be diagnosed in an individual with an unequivocally affected first-degree relative.

Chikumi et al. (2000) stated that more than 137 different FBN1 mutations had been reported. In Japanese patients, they identified 2 additional novel mutations and a recurrent de novo mutation, IVS2DS+1G-A (134797.0035).

Collod-Beroud et al. (1998) stated that over 137 FBN1 mutations had been reported and that these were spread throughout most the gene. Most of them are missense mutations, affecting either the conserved cysteine residues or residues of the calcium-binding consensus sequence of the calcium-binding EGF (cbEGF) motifs.

Fibrillin-1 consists mainly of 47 EGF domains, 43 of which are cbEGF domains, and 7 TGFBR1 (190181)-like (TB) domains interspersed among them. McGettrick et al. (2000) used proteases to probe structural changes caused by the asn2144-to-ser FBN1 calcium-binding mutation (134797.0009) in a TB6-cbEGF32 and a cbEGF32-33 domain pair, and a protein-engineered asn2183-to-ser mutation in the cbEGF32-33 pair. N-terminal sequence analysis of domain pairs digested in the presence and absence of calcium showed that domain interactions between TB6 and cbEGF32 are calcium-independent; domain interactions between cbEGF32 and cbEGF33 are calcium-dependent; and an asn-to-ser mutation causes increased proteolytic susceptibility only when located in cbEGF33, suggesting a key role for interdomain calcium-binding in rigidifying cbEGF domain linkages. The authors concluded that the structural consequences of calcium-binding mutations in fibrillin-1 cbEGF domains may be influenced by domain context.

Most extracellular proteins consist of various modules with distinct functions, e.g., the cbEGF module, mutations in which can lead to a variety of genetic disorders. Reinhardt et al. (2000) described structural and functional consequences of 2 typical mutations in cbEGF modules of fibrillin-1 that result in Marfan syndrome: N548I (134797.0010) and E1073K (134797.0038). Large wildtype and mutated polypeptides were recombinantly expressed in mammalian cells. Neither mutation altered synthesis and secretion of the polypeptides into the culture medium. Electron microscopy showed minor structural differences between wildtype and mutated forms. Mutated polypeptides were significantly more susceptible to proteolytic degradation by a variety of proteases as compared with their wildtype counterparts. Most of the sensitive cleavage sites were mapped close to the mutations, indicating local structural changes within the mutated cbEGF modules. Other cleavage sites, however, were observed at distances beyond the domain containing the mutation, suggesting longer range structural effects within tandemly repeated cbEGF modules. Reinhardt et al. (2000) suggested that proteolytic degradation of mutated fibrillin-1 may play an important role in the pathogenesis of Marfan syndrome and related disorders. They identified plasmin as a fibrillin-1 degrading enzyme and suggested that it could play a role in degradation of mutated fibrillin-1 in a pathologic situation since it has wide substrate specificity and is available in extracellular matrices at sites where fibrillin-1 and microfibrils are expressed. With smooth muscle cell proliferation, macrophage infiltration metalloproteases may be released, potentially enhancing fibrillin-1 degradation as disease progresses.

In cultured human dermal fibroblasts treated with recombinant fibrillin-1 fragments containing the RGD (arg-gly-asp) integrin-binding motif of fibrillin-1, Booms et al. (2005) observed significant upregulation of the matrix metalloproteinases MMP1 (120353) and MMP3 (185250). They suggested that fibrillin fragments might have pathogenic effects by leading to upregulation of MMPs, which might in turn be involved in the progressive breakdown of microfibrils thought to play a role in MFS.

The G1127S mutation in FBN1 (134797.0021) is located in cbEGF13, and experiments on isolated cbEGF13 and a cbEGF13-14 pair indicated that the mutation caused defective folding of cbEGF13, but not cbEGF14. Whiteman et al. (2001) examined the structural consequences of the G1127S mutation in a covalently linked cbEGF12-13 pair and a cbEGF12-14 triple-domain construct. Their findings suggested that covalent linkage of cbEGF12 preserves the native-like fold of cbEGF13 with G1127S, and that conformational effects introduced by G1127S are localized to cbEGF13. Whiteman et al. (2001) concluded that missense mutations in FBN1 cbEGF domains can cause short-range structural effects in addition to the long-range effects previously observed with the E1073K mutation in cbEGF12.

Matyas et al. (2002) evaluated denaturing HPLC for mutation detection in Marfan syndrome, concluding that this method is highly sensitive. With a flow chart they planned a strategy for FBN1 mutation screening.

Robinson et al. (2002) stated that at least 337 mainly unique mutations in the FBN1 gene had been reported in the Marfan syndrome. The clinical presentation of the fibrillinopathies caused by FBN1 mutations ranged from isolated ectopia lentis (ECTOL1; 129600) to neonatal Marfan syndrome, which generally leads to death within the first 2 years of life.

Katzke et al. (2002) used temperature-gradient gel electrophoresis (TGGE) screening of all 65 FBN1 exons to study 126 individuals with Marfan syndrome and related fibrillinopathies. They identified a total of 53 mutations, of which 33 were described for the first time. Several mutations were identified in individuals with fibrillinopathies other than classic Marfan syndrome, including aneurysm of the ascending aorta with only minor skeletal anomalies, and several individuals with only skeletal and ocular involvement. The mutation detection rate in this study was 42% overall, but was only 12% in individuals not fulfilling the diagnostic criteria of Marfan syndrome, suggesting that clinical overdiagnosis is one reason for a low detection rate observed for FBN1 mutation analysis.

Robinson and Godfrey (2000) provided an extensive review of the molecular physiology and pathophysiology of Marfan syndrome and related fibrillinopathies.

Kodera et al. (2002) sequenced the FBN1 gene in 22 Japanese patients with scleroderma and found that a CT insertion in the 5-prime untranslated region of exon A had a significant negative association with disease.

To investigate the effect of misfolding on the trafficking of fibrillin-1 from fibroblast cells, Whiteman and Handford (2003) studied 3 missense mutations (C1117Y, 134797.0025; C1129Y, 134797.0044; and G1127S, 134797.0021) in the cbEGF13 domain. Both C1117Y and C1129Y, expressed as recombinant fragments of fibrillin-1, were retained and accumulated within cells. Both underwent core glycosylation but lacked the complex glycosylation observed in the secreted wildtype fragment, suggesting retention in the endoplasmic reticulum (ER). Coimmunoprecipitation experiments showed association with the ER chaperone calreticulin (CALR; 109091), but not calnexin (CANX; 114217), 78-kD glucose-regulated protein (HSPA5; 138120), or protein disulfide isomerase (P4HB; 176790). In contrast, G1127S, which caused a moderate change in the EGF domain fold, showed a pattern of glycosylation and trafficking profile indistinguishable from the wildtype fragment. Whiteman and Handford (2003) proposed that G1127S may cause disease through an extracellular dominant-negative effect. They further suggested that the observed ER retention of C1117Y and C1129Y is caused either by an intracellular dominant-negative effect or haploinsufficiency.

Collod-Beroud et al. (2003) provided an update on their database of mutations in the FBN1 gene and described the creation of an FBN1 polymorphism database. They stated that 563 FBN1 mutations had been identified. They provided a tabulation of 56 recurrent mutations found in the FBN1 gene. These included the 3037G-A mutation (134797.0036), which had been reported 6 times, and the IVS46+5 G-A mutation (134797.0039), which had been reported 9 times.

Hutchinson et al. (2003) described an FBN1 deletion patient (46,XXdel(15)(q15q22.1)) whose fibrillin-1 protein and mRNA levels were significantly higher than expected for a single FBN1 allele. RNA analyses identified a variable reduction in total FBN1 transcript (78 to 27%) in 3 related individuals carrying a premature termination codon (PTC)-causing mutation compared with unaffected control individuals. Both pulse-chase analysis of fibrillin-1 biosynthesis and RNase protection analyses demonstrated that these differences were due to variation in the expression of the normal FBN1 allele and not nonsense-mediated decay (NMD) of mutant RNA. The authors suggested that differences in normal FBN1 expression may contribute to the clinical variability seen within families with Marfan syndrome.

Singh et al. (2006) screened the 5-prime alternatively spliced exons B, A, and C of the FBN1 gene in 41 patients with Marfan syndrome or with features of Marfan syndrome but not fulfilling strict interpretation of the Ghent criteria, and who were negative for FBN1 mutations in exons 1 to 65. The authors identified 5 sequence variants in the 5-prime upstream region of the FBN1 gene in 6 unrelated patients, 2 of whom fulfilled the Ghent criteria. Preliminary studies suggested that the variants may interfere with transcription.

Using multiplex ligation-dependent probe amplification (MLPA) and high-density SNP arrays, Matyas et al. (2007) analyzed the FBN1 gene in 101 unrelated individuals with MFS or related phenotypes in whom no mutations had been detected by standard genetic testing. In 2 patients with MFS, they identified large FBN1 deletions of 26.8 kb and 302.5 kb (134797.0048), respectively. Negative family histories suggested that both deletions arose de novo. Both deletions involved the putative regulatory and promoter regions of the FBN1 gene; true haploinsufficiency was confirmed by transcript analysis in 1 patient.

Whiteman et al. (2007) showed that an FBN1 fragment (cbEGF11-22) containing any of 4 pathogenic substitutions that inhibit calcium binding in cbEGF13 altered the folding of wildtype cbEGF12, resulting in retention of the cbEGF11-22 fragment in the ER.

Comeglio et al. (2007) analyzed the FBN1 gene in 508 consecutive patients and identified mutations in 90 (82%) of 110 patients with a diagnosis of 'classic' Marfan syndrome, 84 (27%) of 315 with an 'incomplete Marfan phenotype,' and 19 (50%) of 38 patients with isolated ectopia lentis. No mutations were detected in 45 patients with isolated ascending thoracic aortic aneurysm (see 607086).

Aragon-Martin et al. (2010) analyzed the FBN1 gene in 36 UK patients with ectopia lentis who did not fulfill the Ghent criteria for Marfan syndrome and identified causative mutations in 23 (64%), primarily in the 5-prime region of the gene. The authors noted that this represented an improved mutation detection rate over their previous study (Comeglio et al., 2007), due to rescreening of patients who were negative for mutation by SSCA with the more sensitive dHPLC detection method.

Brautbar et al. (2010) reported 3 patients with descending thoracic aortic dissections who were subsequently found to have heterozygous mutations in the FBN1 gene (see, e.g., 134797.0067). All 3 had aortic root dilation, but displayed few of the skeletal features of Marfan syndrome. Two of the 3 had a history of long-term hypertension, and such a history was suspected in the third patient. Brautbar et al. (2010) suggested that there are individuals with FBN1 mutations who have mild nonvascular involvement but significant aortic disease, in whom superimposed factors such as long-term hypertension may weaken the aortic wall and lead to the overt clinical phenotype. They proposed that all patients with descending thoracic aortic dissection be screened for connective tissue disease, with FBN1 sequencing in certain cases.

Yang et al. (2012) studied a 5-generation Chinese family in which 16 members were affected with isolated ectopia lentis and identified a heterozygous missense mutation in the FBN1 gene (R974C; 134797.0063) that segregated with disease. Yang et al. (2012) reviewed published reports and stated that 18 FBN1 mutations associated with isolated ectopia lentis had been found, 3 of which had also been found in association with Marfan syndrome in different families; they also noted that 15 of the mutations were cysteine substitutions.

Marfanoid-Progeroid-Lipodystrophy Syndrome

In a patient with marfanoid-progeroid-lipodystrophy syndrome (MFLS; 616914), Graul-Neumann et al. (2010) identified heterozygosity for a 2-bp deletion in exon 64 of the FBN1 gene (134797.0064) and excluded mutations in the TGFBR1 (190181) and TGFBR2 (190182) genes. The 27-year-old German woman fulfilled the clinical Ghent criteria for Marfan syndrome with 3 major features, including ectopia lentis, aortic dilatation, and dural ectasia, but also showed an extreme reduction in the amount of subcutaneous fat tissue since birth and had prominent facial lipodystrophy.

In a 20-year-old Irish man with Marfan lipodystrophy syndrome, Goldblatt et al. (2011) identified a heterozygous 20-bp deletion in exon 64 of the FBN1 gene (134797.0065) resulting in a frameshift and stop codon at the same relative location in the mRNA as that found by Graul-Neumann et al. (2010).

Horn and Robinson (2011) reported a 3.5-year-old girl who had progeroid facial signs of neonatal onset, large head with corresponding hydrocephaly, decreased subcutaneous fat, and tall stature at the end of infancy. Echocardiography revealed mild mitral valve prolapse. She did not fulfill the Ghent criteria for ocular or cardiovascular manifestations of Marfan syndrome at last examination, but her tall stature, arachnodactyly, and facial gestalt, which was similar to that of the patient reported by Graul-Neumann et al. (2010), prompted analysis of the FBN1 gene, in which a de novo heterozygous splice site mutation in intron 64 was identified (134797.0066).

In a 10-year-old Japanese girl with severe congenital lipodystrophy and neonatal progeroid appearance, accelerated growth in height with poor weight gain, and characteristic facial appearance as well as craniosynostosis, Takenouchi et al. (2013) identified heterozygosity for an 8-bp deletion in exon 64 of the FBN1 gene (134797.0069).

In a 16-year-old girl with Marfan lipodystrophy syndrome, Jacquinet et al. (2014) identified heterozygosity for a de novo splice site mutation in intron 64 of FBN1 (134797.0070). The authors noted that all reported mutations in MFLS patients result in a truncated mRNA predicted to encode a shorter protein with an altered protein sequence at the C terminus.

In 2 female patients with congenital partial lipodystrophy and a progeroid appearance, Romere et al. (2016) identified heterozygosity for truncating mutations in exon 64 of the FBN1 gene (see, e.g., 134797.0066). No additional clinical information was provided. Romere et al. (2016) also studied the C-terminal cleavage product of profibrillin, which they designated 'asprosin' after the Greek word for white, because of the reduction in subcutaneous white adipose tissue displayed by asprosin-deficient patients. Both of their patients showed lower levels of asprosin than would be expected with a heterozygous genotype, suggesting a dominant-negative effect.

Weill-Marchesani Syndrome 2

Faivre et al. (2003) analyzed the FBN1 gene in 2 families segregating autosomal dominant Weill-Marchesani syndrome (WMS2; 608328) that mapped to chromosome 15q21.1, and identified a heterozygous 24-bp deletion in 1 of the families (134797.0040).

Stiff Skin Syndrome

Loeys et al. (2010) sequenced the FBN1 gene in probands from 4 unrelated families with stiff skin syndrome (SSKS; 184900) and identified heterozygous missense mutations in each, all within exon 37 of the gene (see 134797.0050-134797.0053, respectively). Another patient who had a 'hybrid' phenotype of stiff skin syndrome with ectopia lentis was found to be heterozygous for a missense mutation in exon 38 of FBN1 (134797.0054). Loeys et al. (2010) noted that all of the stiff skin syndrome-associated mutations occurred within the fourth TGFB (TGFB1; 190180)-binding protein-like domain (TB4) of FBN1, which encodes the only RGD sequence in fibrillin-1, a motif that mediates cell-matrix interactions via integrin binding. In studies in human foreskin dermal fibroblasts (FS2 cells), the W1570C (134797.0050 and 134797.0051) and C1564S (134797.0052) mutations induced a marked loss of both attachment and spreading of FS2 cells compared to wildtype, suggesting impairment of interaction with alpha-V-beta-3 and possibly alpha-5-beta-1 integrins (see 193210 and 135620). Human endometrial stromal fibroblasts (hESF cells) also failed to attach or spread when plated on mutant substrates, and cultured dermal fibroblasts from patients with stiff skin syndrome showed reduced amounts of the activated (phosphorylated) form of focal adhesion kinase, an event mediated by the interaction of RGD ligands with integrins concentrated at focal adhesions. Loeys et al. (2010) suggested that FBN1 mutations that cause stiff skin syndrome can impair integrin binding and signaling.

Geleophysic Dysplasia 2 and Acromicric Dysplasia

In 29 patients with geleophysic dysplasia-2 (GPHYSD2; 614185) and 10 with acromicric dysplasia (ACMICD; 102370), Le Goff et al. (2011) performed exome sequencing followed by candidate gene analysis and identified heterozygosity for 16 different mutations in the FBN1 gene, respectively (see, e.g., 134797.0055-134797.0060), 2 of which were found both in patients with geleophysic dysplasia-2 and in patients with acromicric dysplasia. Both disorders are characterized by short stature, short hands and feet, joint limitations, and thickened skin, but geleophysic dysplasia patients also have cardiorespiratory involvement that often leads to early death. Le Goff et al. (2011) concluded that geleophysic dysplasia and acromicric dysplasia are clinically distinct but allelic conditions. All of the mutations identified in these patients were located in exons 41 and 42, encoding the TGFB-binding protein-like 5 domain (TB5) of FBN1, and none were found in 2,000 ethnically matched controls or in the Marfan mutation database. Microfibrillar network disorganization and enhanced TGFB signaling were consistent features in fibroblasts from both geleophysic and acromicric dysplasia patients.


Genotype/Phenotype Correlations

Palz et al. (2000) analyzed the terminal 7 exons (exons 59-65) of the FBN1 gene in 124 unrelated patients with MFS and identified 5 novel mutations. Their findings, together with the findings of the review by Collod-Beroud et al. (1998), showed that about 40% (8/20) of the mutations in exons 59-65 are associated with a mild phenotype characterized by a lack of aortic root pathology. In contrast, only about 7% of mutations reported in the remainder of the gene resulted in a mild phenotype without aortic root pathology, even when the mutation occurred in the same position in the cbEGF motif. The authors noted that observations suggesting that the N-terminal portion of FBN1 but not the C-terminal portion is required for incorporation into polymeric microfibrils (Lonnqvist et al., 1998) and for the homodimerization of fibrillin monomers (Trask et al., 1999) may provide an explanation for the proposed loose phenotype-genotype correlation.

Tiecke et al. (2001) analyzed exons 24-40 of the FBN1 gene by temperature-gradient gel electrophoresis in 124 unrelated patients with Marfan syndrome and identified 12 probable disease-causing mutations, 10 of which were novel. A recurrent mutation (G1013R; 134797.0036) in exon 24 was found in 2 unrelated patients with atypically severe clinical manifestations. Their results, together with those in other reports, showed that 12 of 14 missense mutations in patients with atypically severe MFS clustered in exons 24-32, suggesting a critical functional role for this region. Atypically severe MFS was characterized by cardiovascular complications requiring surgery in childhood as well as by abnormal face and ears, with or without congenital contractures. Missense mutations associated with neonatal MFS were found primarily in exons 25 and 26. Despite the clustering of mutations associated with neonatal and atypically severe MFS, mutations associated with classic MFS occurred in the same region. Based on these findings, Tiecke et al. (2001) concluded that there was no way of predicting whether a given mutation in exons 24-32 would be associated with classic, atypically severe, or neonatal MFS.

To correlate genotype with phenotype and define the subtype of fibrillinopathy caused by premature termination codon mutations, Schrijver et al. (2002) integrated genotype information and mRNA expression levels with clinical and biochemical phenotypes. By screening the entire FBN1 gene for mutations, they identified 34 probands with premature termination codon mutations. With the exception of 2 recurrent mutations, the nonsense and frameshift mutations were unique and spanned the entire FBN1 gene, from IVS2 to IVS63. Allele-specific RT-PCR reaction analyses revealed differential allelic expression in all studied samples, with variable reduction of the mutant transcript. Fibrillin protein synthesis and deposition into the extracellular matrix were studied by pulse-chase analysis of cultured fibroblasts. In most premature termination codon samples, synthesis of normal-sized fibrillin protein was approximately 50% of control levels, but matrix deposition was disproportionately decreased. Only 22 of 31 (71%) probands and 14 of 24 (58%) mutation-positive family members met clinical diagnostic criteria for MFS. The group with premature termination codon showed statistically significant differences in the frequency of individual signs, especially in the ocular manifestations, when compared with the previously reported study group of 44 individuals with FBN1 cysteine substitutions (Schrijver et al., 1999). Large-joint hypermobility was more common in the premature termination codon group, and lens dislocation and retinal detachment were less common. Schrijver et al. (2002) concluded that premature termination codon mutations have a major impact on the pathogenesis of type 1 fibrillinopathies and convey a distinct biochemical, clinical, and prognostic profile.

Loeys et al. (2004) undertook a study of the FBN1 gene in a cohort of 93 Marfan syndrome patients fulfilling the clinical diagnosis of the disorder according to the Ghent nosology. An initial mutation screening by CSGE/SSCP allowed identification of an FBN1 mutation in 73 patients. Then, sequencing of all exons of the FBN1 gene was performed in 11 mutation-negative patients, while in 9 others, DHPLC was used. This allowed identification of 7 and 5 additional mutations, respectively. Southern blot analysis revealed an abnormal hybridization pattern in 1 more patient. A total of 23 of the 85 mutations identified were reported by Loeys et al. (2004) for the first time. Phenotypic comparison of Marfan syndrome patients with cysteine-involving mutations versus premature termination mutations revealed significant differences in ocular and skeletal involvement. As described by Schrijver et al. (2002), PTC mutations appeared to be associated with more severe skeletal findings, whereas the cysteine substitution was associated with significantly greater incidence of ectopia lentis.

Rommel et al. (2005) analyzed the FBN1 gene in 116 patients with Marfan syndrome and identified 29 novel and 9 recurrent FBN1 mutations in 38 patients. Genotype-phenotype correlations showed a significantly lower incidence of ectopia lentis in patients who carried a mutation that led to a premature termination codon or a missense mutation without cysteine involvement in FBN1, as compared to patients whose mutations involved a cysteine substitution or splice site alteration.

Faivre et al. (2007) analyzed genotype/phenotype correlations in 1,013 probands with a pathogenic FBN1 mutation registered in the international FBN1 Universal Mutation Database (Collod-Beroud et al., 2003). A total of 803 pathogenic mutations were found in the 1,013 probands, including 114 recurrent mutations in 324 probands. Five hundred and forty-two of the 1,013 probands (54%) had ectopia lentis. The higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an in-frame mutation. Mutations in exons 24 through 32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; most of these results were replicated even when cases of neonatal MFS were excluded. Faivre et al. (2007) suggested that these correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant-negative vs haploinsufficiency) and by consideration of the 2 main physiologic functions of fibrillin-1 (structural vs mediator of TGF-beta signaling). Exon 24 through 32 mutations defined a group at high risk for cardiac manifestations associated with severe prognosis at all ages.

Faivre et al. (2007) pointed out the strong correlation between ectopia lentis and the presence of a mutation affecting a cysteine residue, and the fact that a main feature distinguishing the phenotype associated with mutations in TGFBR1 (190181) and TGFBR2 (190182) is the almost consistent absence of ocular involvement in the latter patients. Thus, it could be speculated that the functional aspect of fibrillin-1 that is altered in patients with ectopia lentis is not involved in TGF-beta signaling but is a structural function of the extracellular matrix. Correct cysteine localization and disulfide bonding appears to play an important role in the structural integrity of the suspensory ligament of the lens. On the other hand, the strong correlation between FBN1 premature termination codon (PTC) mutations and severe skeletal and skin phenotypes of a type associated also with TGFBR1/2 mutations suggests that a function or pathway common to fibrillin-1 and the TGF-beta type 1/2 receptors is altered in these patients. It could be speculated that haploinsufficiency for fibrillin-1 in bone and skin has a stronger affect on the TGF-beta signaling function of the protein than on its structural function--and thus that, in bone growth, fibrillin-1 acts as a mediator of TGF-beta signaling.

Blyth et al. (2008) reported 2 unrelated girls with severe early-onset Marfan syndrome who were found by MLPA dosage analysis to have exonic deletions in the FBN1 gene (see, e.g. 134797.0049). One patient was a somatic mosaic for the deletion. The authors suggested that Marfan patients with FBN1 deletions have a more severe phenotype than those with missense mutations.

Attanasio et al. (2008) identified FBN1 mutations in 75 (88%) of 85 patients with MFS and in 5 (36%) of 14 patients with a type I fibrillinopathies that did not meet the diagnostic criteria for MFS. Forty-six of 77 mutations were novel. The majority of missense mutations were within the calcium-binding EGF-like domains. There were preferential associations between cys-related missense mutations and ectopia lentis, and premature termination codon mutations and skeletal manifestations. In contrast to what had been reported in the literature, the cardiovascular system was severely affected also in patients carrying mutations in exons 1 to 10 and 59 to 65.

Faivre et al. (2009) analyzed the phenotypic characteristics of 198 probands (20%) with a mutation in exons 24 through 32 of the FBN1 gene from a series of 1,013 probands with an FBN1 mutation. Patients with mutations leading to a premature termination codon within exons 24 through 32 had a more severe phenotype with a significantly higher probability of developing ectopia lentis and mitral insufficiency compared to patients with in-frame mutations in the same region. Patients with a truncation mutation between exons 24 through 32 rarely displayed a neonatal or severe MFS presentation. However, those with mutations in exon 25, which encodes the eleventh EGF-like domain, had a higher probability of neonatal presentations and cardiovascular manifestations. Recurrent mutations were associated with high phenotypic heterogeneity ranging from neonatal to classical MFS phenotype.

Faivre et al. (2009) analyzed the clinical and molecular characteristics of 146 adult probands with known FBN1 mutations who did not fulfill the Ghent criteria for Marfan syndrome. The authors found at least 1 component of the Ghent nosology, insufficient alone to constitute a minor criterion, in 12 of 17 patients with isolated dilation of the ascending aorta and in 9 of 12 patients with isolated ectopia lentis. They stated that analysis of recurrent mutations and of affected family members of probands with only 1 major clinical criterion argued for a clinical continuum between such phenotypes and classic Marfan syndrome. Faivre et al. (2009) concluded that, using strict definitions, patients with FBN1 mutations and only 1 major clinical criterion or with only minor clinical criteria of 1 or more organ systems do exist, but represent only 5% of the adult cohort.

Stheneur et al. (2009) analyzed the FBN1 gene in 586 unrelated patients referred for molecular diagnosis, including 21 cases of neonatal MFS, 21 children with probable MFS, 105 adults with incomplete MFS, 266 adults with classic MFS, 21 adults with non-MFS, 15 patients with other diagnoses, and 137 patients excluded from statistical analysis. The mutation detection rate was 72.5% in probands with classic MFS, 58% in those referred for incomplete MFS, and only 14.3% for those referred as non-MFS. Recursive partitioning statistical analysis showed that, among the different variables tested, the most significant was the number of organ systems involved, and the second most significant was the presence of ectopia lentis. Stheneur et al. (2009) concluded that the best predictor for identification of an FBN1 mutation is the presence of features in at least 3 organ systems, combining 1 major and various minor criteria. They noted that the earlier recommendation of 2 systems involved with at least 1 major criterion represents the minimal criteria, because the mutation detection rate falls dramatically in probands not meeting those criteria.

Using DNA samples from 300 patients with clinical features of MFS or a related phenotype that had been previously screened by DHPLC with no mutations found in the FBN1 gene, Hilhorst-Hofstee et al. (2011) performed MLPA and identified 9 patients from 5 families with deletion of 1 entire FBN1 allele. A tenth patient with complete deletion of FBN1 was identified by cytogenetic analysis and array CGH. All of the patients had facial and skeletal features of MFS, and 7 of the 10 patients fulfilled the Ghent criteria; the 3 patients who did not present the full clinical picture of MFS were young (5, 8, and 13 years of age, respectively). Aortic root dilation was present in 6 patients, 2 of whom underwent surgical repair at relatively young ages. Hilhorst-Hofstee et al. (2011) concluded that complete loss of 1 FBN1 allele does not predict a mild phenotype, and that their findings supported the hypothesis that true haploinsufficiency can lead to the classic phenotype of Marfan syndrome.

In cultures of transiently transfected HEK293 cells, Jensen et al. (2015) demonstrated that MFS-associated substitutions involving domains TB4 and TB5 of FBN1 (C1564Y, C1719Y, and C1720Y) result in a loss of fibrillin-1 from the cell culture medium, whereas mutants associated with stiff skin syndrome (C1564S, 134797.0052; W1570C, 134797.0050 and 134797.0051) or the acromelic dysplasias (e.g., G1762S, 134797.0056) are secreted into the extracellular media. The stiff skin syndrome and acromelic dysplasia-associated mutants were further shown to incorporate into the microfibril network produced by fibroblasts in culture. Jensen et al. (2015) suggested that stiff skin syndrome and the FBN1-associated acromelic dysplasias, including geleophysic dysplasia-2 and acromicric dysplasia, result from postassembly changes in microfibril interactions, whereas MFS results from a loss of microfibrils. The authors proposed that aberrant TGFB signaling observed in each of the FBN1-associated diseases is due to different causes: in MFS, it is be due to loss of structural integrity in the fibrillin matrix, affecting TGFB activation through a change in the mechanical properties of tissues, whereas in stiff skin syndrome and the acromelic dysplasias, it more likely involves defective cell-surface interactions with microfibrils, resulting in TGFB dysregulation, fibrosis, and dermal accumulation of microfibril aggregates as a secondary response to an altered signaling program.

Takenouchi et al. (2013) reviewed 4 patients with Marfan lipodystrophy syndrome who all had mutations in exon 64 of FBN1. The authors noted that the frameshift mutations in 3 of the patients resulted in a common aberrant motif, ETEKHKRN, at the carboxyl termini of the transcripts, and suggested that this motif might be associated with the phenotype.

Variant Classification

Using FBN1-specific criteria and American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) 2015 guidelines for variant interpretation, Baudhuin et al. (2019) reanalyzed 674 FBN1 missense variants from 18 submitters to the ClinVar database. Of the 674 missense variants, 140 (20.8%) had more than 1 submitter, and 43 (30.7%) of the latter had discrepant classifications. Using gene-based knowledge, the authors were able to resolve all 43 missense variants that had discrepant multisubmitter ClinVar classifications, and also to revise variant calls in 150 (23.8%) of the remaining 631 FBN1 missense variants. Baudhuin et al. (2019) noted that many ClinVar entries did not contain substantive evidence to support their classification, and that variants without supporting data are of very little value. In the absence of phenotypic data, however, they concluded that variant classification can be refined using gene-based evidence.


Gene Therapy

There is a considerable body of evidence that many FBN1 mutant alleles lead to Marfan syndrome through a dominant-negative effect (Dietz and Pyeritz, 1995 Eldadah et al., 1995). Since this raises the possibility that reduction of the amount of mutant FBN1 might be a valid therapeutic approach for treating Marfan syndrome, Kilpatrick et al. (1996) designed and synthesized a trans-acting hammerhead ribozyme (see Cech and Bass, 1986) targeted to the 5-prime end of the human FBN1 mRNA. They noted that potential hammerhead ribozymes which possess a catalytic domain and flanking sequence complementary to a target mRNA, can cleave the target mRNA molecule in trans at a 3-base target sequence. Kilpatrick et al. (1996) delivered the ribozyme into cultured dermal fibroblasts by receptor-mediated endocytosis of a ribozyme-transferrin-polylysine complex. They noted that successful delivery of the ribozyme reduced both cellular FBN1 mRNA and the deposition of fibrillin in the extracellular matrix. Kilpatrick et al. (1996) concluded that the sensitivity of hammerhead ribozymes to mismatches between ribozyme and target sequences supports the feasibility of designing ribozymes to target mutant FBN1 alleles.

Antisense technologies for the targeted inhibition of gene expression could provide an effective strategy for the management of inherited disorders with dominant-negative or gain-of-function pathogenetic mechanisms, for the suppression of oncogenes, or for the control of a variety of infectious agents. In situ expression of antisense complementary RNA (cRNA) has many theoretical and practical advantages over methods based on the exogenous administration of synthetic oligodeoxynucleotides which have a propensity for producing non-sequence-specific biologic effects. For in vivo therapeutic applications, foremost among these advantages is the potential for enduring activity. Many naturally occurring cRNAs with well-documented regulatory functions have been described in prokaryotes. All are characterized by stable stem-loops that encompass or flank the targeting sequence, with the 3-prime loop generally having a high GC content. These structures are believed to enhance stability of the targeting molecules by conferring resistance to the activity of exonucleases. Montgomery and Dietz (1997) fashioned an antisense expression construct to mimic selective properties of naturally occurring antisense RNAs in prokaryotes for efficient inhibition of gene expression by in situ-expressed recombinant molecules in mammalian cells. Prokaryotic regulatory transcripts are expressed at high levels and have hairpin structures at their termini, features reminiscent of small nuclear RNAs (snRNAs) which are abundant and stable in the nucleus of all mammalian cells. Montgomery and Dietz (1997) substituted a sequence complementary to fibrillin-1 mRNA, interrupted in its center by a hammerhead ribozyme, for the Sm protein binding site between the stem-loop structures of U1 snRNA. Expression of the chimeric antisense RNA resulted in dramatic inhibition of expression of fibrillin-1 message and protein in stably transfected cultured cells. The inhibitory effect was localized to the nucleus. They suggested that the biologic properties of U1 snRNA may provide a widely applicable vehicle for the in vivo delivery of antisense targeting sequences. Use of this approach in Marfan syndrome would allow the application of a single strategy to all patients despite allelic heterogeneity.


Animal Model

'Tight-Skin' Mouse

Green et al. (1976) described a novel mouse mutant, 'tight-skin' (Tsk). Heterozygotes had tight skin with marked hyperplasia of subcutaneous loose connective tissue. Increased growth of cartilage and bone was a feature. Tendons were small with hyperplasia of the sheaths. Homozygotes died in utero. Growth hormone was normal. The authors speculated that the mutation may cause defective cell receptors with high affinity for a somatomedin-like factor promoting growth of connective tissue.

Muryoi et al. (1991) showed that Tsk mice spontaneously produce anti-topoisomerase I antibodies, which are characteristically found only in patients with progressive systemic sclerosis (181750) but not in patients with the CREST syndrome, a systemic sclerosis-related disorder. The autoantibodies produced in the tight-skin mouse are encoded primarily by heavy-chain variable genes from the J558 family. Kasturi et al. (1994) showed that the J558 genes encoding these antibodies are not derived from a selected germline gene(s) or a single subfamily but rather from genes belonging to diverse J558 subfamilies. All the results strongly suggested that the establishment of the autoimmune repertoire is mediated by V(H)-gene-dependent selection of B cells, though the contribution of an antigen-mediated selection mechanism could not be ruled out.

Siracusa et al. (1993) localized the Tsk mutation with respect to known molecular markers on mouse chromosome 2. Everett et al. (1994) showed that Tsk is closely linked to the gene for bone morphogenetic protein-2A (112261). Using an interspecific backcross, Doute and Clark (1994) carried out positional cloning of Tsk and determined linkage to several genetic markers in the following order on mouse chromosome 2: pa-B2m-Tsk-Fbn-1-II-1a-a.

The Tsk locus maps to a region on chromosome 2 that includes a segment that is syntenic with human chromosome 15 (Doute and Clark, 1994). Since the microfibrillar glycoprotein gene fibrillin-1 is located on human 15q, it became a candidate for the Tsk mutation in the mouse. Siracusa et al. (1996) demonstrated that the Tsk chromosome harbors a 30- to 40-kb genomic duplication within the Fbn1 gene that results in a larger than normal in-frame Fbn1 transcript. The findings provided possible explanations for the phenotypic features of Tsk/+ mice and the lethality of Tsk/Tsk embryos. Siracusa et al. (1996) noted that the Tsk mouse has been used as a model for several human diseases, including stiff skin syndrome (SSKS; 184900).

Kielty et al. (1998) examined the consequences of the mouse Tsk mutation. Dermal fibroblasts from heterozygous mice synthesized and secreted both normal fibrillin and a mutant oversized fibrillin in comparable amounts, and Tsk fibrillin-1 was stably incorporated into cell layers. Studies by several methods indicated that Tsk fibrillin-1 polymerizes and becomes incorporated into a discrete population of beaded microfibrils with altered molecular organization.

The protein encoded by the mutant Tsk gene is larger (418 kD) than the normal (350 kD) fibrillin protein. Gayraud et al. (2000) found that mice compound heterozygous for the Tsk mutation and hypomorphic Fbn1 alleles displayed both Tsk and MSF traits. Further studies suggested that bone and lung abnormalities of Tsk/+ mice are due to copolymerization of mutant and wildtype molecules into functionally deficient microfibrils. Vascular complications were thought to be absent in these animals because the level of functional microfibrils does not drop below the critical threshold. Indirect in vitro evidence suggested that a potential mechanism for the dominant-negative effects of incorporating Tsk fibrillin-1 into microfibrils is increased proteolytic susceptibility conferred by the duplicated Tsk region.

Saito et al. (2002) found that B cells of Tsk/+ mice, a model for human systemic sclerosis, had decreased IgM expression, enhanced serum IgG production, spontaneous autoantibody production, and enhanced Cd19 (107265) tyrosine phosphorylation, Vav (164875) phosphorylation, and Lyn (165120) kinase activity. Tsk/+ mice deficient in Cd19 expression showed decreased skin fibrosis, upregulated surface IgM expression, abrogation of hypergammaglobulinemia and autoantibody production, and inhibition of Il6 (147620) production. Saito et al. (2002) concluded that chronic B-cell activation resulting from augmented Cd19 signaling in Tsk/+ mice leads to skin sclerosis and autoimmunity, possibly through overproduction of Il6.

Gerber et al. (2013) generated 2 Fbn1-targeted mouse models of stiff skin syndrome (184900), one harboring a W1572C mutation, which is equivalent to human W1570C (134797.0050 and 134797.0051), and the other harboring a D1545E mutation, which eliminates the RGD motif needed to mediate cell-matrix interactions by binding to cell surface integrins. Gerber et al. (2013) showed that mouse lines harboring these mutations recapitulated aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the profibrotic cytokine transforming growth factor-beta (TGFB). Mutant mice showed skin infiltration of proinflammatory immune cells, including plasmacytoid dendritic cells, T helper cells, and plasma cells, as well as autoantibody production. These findings were normalized by integrin-modulating therapies or TGFB antagonism. Gerber et al. (2013) concluded that the results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programs and highlight new therapeutic strategies for systemic sclerosis (181750).

Marfan Syndrome Models

It was believed that microfibrils, of which fibrillin-1 is the major constituent, regulated elastic fiber formation by guiding tropoelastin deposition during embryogenesis and early postnatal life. Hence, vascular disease in Marfan syndrome was thought to result when FBN1 mutations precluded elastic fiber maturation by disrupting microfibrillar assembly. However, Pereira et al. (1997) performed a gene-targeting experiment in mice that indicated that fibrillin-1 microfibrils are predominantly engaged in tissue homeostasis rather than elastic matrix assembly. This finding, in turn, suggested that aortic dilation is due primarily to the failure by the microfibrillar array of the adventitia to sustain physiologic hemodynamic stress, and that disruption of the elastic network of the media is a secondary event.

A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax). To investigate the pathogenesis of genetically imposed emphysema, Neptune et al. (2003) analyzed the lung phenotype of mice deficient in fibrillin-1 (Pereira et al., 1997). Lung abnormalities were evident in the immediate postnatal period and were manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 developed destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. Neptune et al. (2003) showed that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-beta-1 (TGFB1; 190180) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta by means of a TGF-beta-neutralizing antibody attenuated apoptosis and rescued alveolar septation in vivo. These data indicated that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease. Kaartinen and Warburton (2003) discussed the general implications of the finding that fibrillin controls TGF-beta activation.

Ng et al. (2004) examined mitral valves from fibrillin-1 null mice and found postnatally acquired alterations in architecture that correlated both temporally and spatially with increased cell proliferation, decreased apoptosis, and excess TGF-beta activation and signaling. TGF-beta antagonism in vivo rescued the valve phenotype. Expression analyses identified increased expression of numerous TGF-beta-related genes that regulate cell proliferation and survival. Ng et al. (2004) suggested that TGF-beta is a mediator of myxomatous mitral valve disease.

A dominant-negative mechanism has been inferred for the pathogenesis of Marfan syndrome based upon dominant inheritance, multimerization of monomers to form microfibrils, and the dramatic paucity of matrix-incorporated fibrillin-1 seen in heterozygous patient samples. Judge et al. (2004) presented evidence for a critical role of haploinsufficiency in the pathogenesis of Marfan syndrome. Yeast artificial chromosome-based transgenesis was used to overexpress the disease-associated cys1663-to-arg mutant form of human fibrillin-1 (C1663R; 134797.0006) on a normal mouse background. The mice failed to show any abnormalities of cellular or clinical phenotype despite regulated overexpression of mutant protein in relevant tissues and developmental stages and despite direct evidence that mouse and human fibrillin-1 interact with high efficiency. Immunostaining with a human-specific monoclonal antibody demonstrated that mutant fibrillin-1 can participate in productive microfibrillar assembly. Use of homologous recombination to generate mice heterozygous for a missense mutation comparable to C1663R (i.e., C1039G) revealed impaired microfibrillar deposition, skeletal deformity, and progressive deterioration of aortic wall architecture, comparable to characteristics of the human condition. The data were considered consistent with a model that invokes haploinsufficiency for wildtype fibrillin-1, rather than production of mutant protein, as the primary determinant of failed microfibrillar assembly. In keeping with this model, introduction of a wildtype FBN1 transgene on a heterozygous C1039G background rescued aortic phenotype. In commenting on the work of Judge et al. (2004), Byers (2004) reviewed the evidence that fibrillin is more than a structural protein. The interrelationship with TGF-beta was reviewed with a diagram adapted from Kaartinen and Warburton (2003). Byers (2004) suggested that TGF-beta blockade may be used in preference to beta-adrenergic blockade as a more effective treatment of many aspects of Marfan syndrome.

Using the Fbn1(mgR/mgR) mouse model of Marfan syndrome, Cook et al. (2014) determined that dilated cardiomyopathy (DCM) in fibrillin-1-deficient mice is a primary manifestation of extracellular matrix (ECM)-induced abnormal mechanosignaling by cardiomyocytes. MFS mice displayed spontaneous emergence of an enlarged and dysfunctional heart, altered physical properties of myocardial tissue, and biochemical evidence of chronic mechanical stress, including increased AGTR1 (106165) signaling and abated focal adhesion kinase (FAK; 600758) activity. Partial fibrillin-1 gene inactivation in cardiomyocytes was sufficient to precipitate DCM in otherwise phenotypically normal mice. Consistent with abnormal mechanosignaling, normal cardiac size and function were restored in MFS mice treated with an AGTR1 antagonist and in MFS mice lacking AGTR1 or beta-arrestin-2 (ARB2; 107941), but not in MFS mice treated with an angiotensin-converting enzyme (ACE; 106180) inhibitor or lacking angiotensinogen. Conversely, Cook et al. (2014) found that DCM associated with abnormal AGTR1 and FAK signaling was the sole abnormality in mice that were haploinsufficient for both fibrillin-1 and beta-1 integrin (ITGB1; 135630). The authors concluded that these findings implicated fibrillin-1 in the physiologic adaptation of cardiac muscle to elevated workload.

Marfanoid-Progeroid-Lipodystrophy Syndrome Models

Duerrschmid et al. (2017) generated C57Bl/6 mice that were heterozygous for a mutation that results in skipping of Fbn1 exon 65, analogous to a mutation (134797.0066) found in patients with Marfan lipodystrophy syndrome, and observed a phenocopy of the human disorder. The mutant mice displayed extreme leanness compared to sex-matched littermates, and DEXA scan revealed reductions in both fat mass and lean mass, with no significant change in body length. When exposed to severe diabetogenic and obesogenic stress, the mutant mice were completely protected from both obesity and diabetes. Similar to the human disorder, the mutant mice exhibited hypophagia as well as a reduction in energy expenditure. In addition, the activity of known orexigenic AgRP+ neurons within the hypothalamus was significantly lower in the mutant mice compared to wildtype mice. A single subcutaneous dose of the C-terminal cleavage product of profibrillin, asprosin, was sufficient to rescue the hypophagia phenotype completely, thus demonstrating that the hypophagia was due to asprosin deficiency rather than an indirect effect of mutated Fbn1. Tagged recombinant asprosin injected intravenously into rats was detected 1 hour later in their cerebrospinal fluid, indicating that plasma asprosin crosses the blood-brain barrier. Treatment with an asprosin-specific antibody significantly reduced intake in wildtype mice of a different genetic background (KK strain), but asprosin neutralization had no effect on food intake in Agouti yellow mice, indicating that asprosin-mediated appetite stimulation requires an intact melanocortin pathway (see POMC, 176830). In Lepr-db/db obese mice, which have a mutation in the leptin receptor (601007), immunologic neutralization of asprosin over 5 days showed reduced food intake and an improvement in body weight.


ALLELIC VARIANTS ( 70 Selected Examples):

.0001 MARFAN SYNDROME, SEVERE CLASSIC

FBN1, ARG1137PRO
  
RCV000017883

In 2 unrelated girls, one Caucasian and one black, with severe classic Marfan syndrome (MFS; 154700), Dietz et al. (1991) found a G-to-C transversion at nucleotide 3410, which converted codon 1137 from CGC (arginine) to CCC (proline). In both cases the mutation was heterozygous and represented a de novo event. After the first affected patient was found, allele-specific oligonucleotides (ASOs), specific for the normal and mutant alleles, were used to screen PCR-amplified genomic DNA from 19 additional patients with sporadic disease, their parents, and an affected individual from each of 24 families with the Marfan syndrome. The second de novo occurrence of R1137P was observed in one of the patients with sporadic disease. None of the other patients showed abnormality. The change in this disorder is nonconservative, replacing a basic amino acid with the nonpolar alpha-amino acid proline. The mutation occurs in an 'EGF-like' repeat, which has homology in Drosophila and C. elegans, suggesting that this is a functionally significant region of the protein. R1137P also occurs at a CpG dinucleotide but does not involve the C-to-T transition usually associated with such mutational 'hotspots.' Recurrent de novo mutation that is not a transition at a CpG dinucleotide has been found also in the factor VIII gene (300841). Although R1137P was the only recurrent mutation identified to that date, its rarity was indicated by the failure to find any example among 180 unrelated Marfan syndrome patients distributed in 3 reported studies (Tynan et al., 1993). This mutation was previously known as ARG239PRO.


.0002 MARFAN SYNDROME, MILD VARIABLE

FBN1, CYS2307SER
  
RCV000017884...

In a family in which multiple members in several generations had the Marfan syndrome (MFS; 154700) with wide variability in the age of onset, organ-system involvement and clinical severity, Dietz et al. (1992) found a cysteine-to-serine substitution at codon 2307 (C2307S) in an EGF-like motif from one fibrillin allele. Twenty individuals were investigated. All 4 living and clinically affected persons carried the mutation. Some affected adults were unaware of their status before the molecular diagnosis. This mutation was previously known as CYS1409SER.


.0003 MARFAN SYNDROME

FBN1, 366-BP DEL
   RCV000017885

Screening 20 unrelated patients with Marfan syndrome (MFS; 154700) for mutations in fibrillin cDNA by single-strand conformation polymorphism analysis, Kainulainen et al. (1992) found 2 with mutations in heterozygous form that resulted in a shortened fibrillin polypeptide. The first mutation was a large in-frame deletion of 366 bases of the fibrillin mRNA, now known to encode exons 60-62, that resulted in a truncated but secreted polypeptide found in the fibroblast culture of the patient. The patient was a 48-year-old man with cardiovascular, eye, and skeletal features of the Marfan syndrome. He was a member of a 3-generation English pedigree, none of whom had ectopia lentis. A brother had had mitral valve replacement at 39 years of age and died suddenly at age 44. A sister also had severe mitral valve prolapse and moderate aortic root dilatation.


.0004 MARFAN SYNDROME

FBN1, G8268A, TRP2756TER
  
RCV000017886...

In a 55-year-old Finnish man with Marfan syndrome (MFS; 154700) manifested by dislocated lenses, retinal detachment, aneurysm of the ascending aorta with aortic regurgitation, and typical skeletal features, Kainulainen et al. (1992) identified a G-to-A transition at nucleotide 8268, predicting premature termination by 116 amino acids. By molecular studies in the family and by family history, the patient appeared to be a sporadic case. This mutation was previously designated as TRP1858TER.


.0005 MARFAN SYNDROME

FBN1, CYS1249SER
  
RCV000017887...

In a patient with childhood presentation of sporadic Marfan syndrome (MFS; 154700), Dietz et al. (1992) found a heterozygous 3746G-C transversion in the FBN1 gene, resulting in a cys1249-to-ser (C1249S) substitution. The patient had ectopia lentis, long-bone overgrowth, scoliosis, mitral valve prolapse, and aortic root dilatation. This mutation was previously designated as CYS351SER.


.0006 MARFAN SYNDROME

FBN1, CYS1663ARG
  
RCV000017888

By SSCP analysis of cDNA, Dietz et al. (1992) detected an abnormally migrating band unique to the sample of the patient with the Marfan syndrome (MFS; 154700). Direct sequencing revealed a T-to-C transition at nucleotide 4987 in 1 FBN1 allele causing the substitution of arginine for cysteine at codon 1663. The patient was adopted as an infant and the medical history for his biologic parents was not available. He had classic and severe features of the Marfan syndrome which presented in early childhood, necessitating surgical intervention for scoliosis and aortic root dilatation. He also had ectopia lentis. This mutation was previously designated as CYS765ARG.


.0007 MARFAN SYNDROME

FBN1, CYS2221SER
  
RCV000017889

In a patient with Marfan syndrome (MFS; 154700) with classic and severe involvement of the ocular, skeletal, and cardiovascular systems, Dietz et al. (1992) found an abnormally migrating fragment on SSCP analysis and showed by direct sequencing a G-to-C transversion in 1 FBN1 allele at nucleotide 6662 causing the substitution of serine for cysteine at codon 2221. This mutation was previously designated as CYS1323SER.


.0008 MARFAN SYNDROME

FBN1, TYR2113TER, EX51DEL
  
RCV000017892...

In a patient with typical Marfan syndrome (MFS; 154700), Dietz et al. (1993) found deletion of exon 51 in the FBN1 cDNA. In the genomic DNA, they demonstrated a T-to-G transversion in 1 allele at position 26 in exon 51. The corresponding amino acid alteration was a substitution of a termination codon for tyrosine at codon 2113 (Y2113X) in the characterized coding sequence of FBN1. This unusual finding represented the skipping of a constitutive exon containing a nonsense mutation. Similar results were observed for 2 nonsense mutations in the OAT gene in patients with gyrate atrophy (see 258870.0036 and 258870.0037). This mutation was previously designated as TYR1215TER. See also Dietz and Kendzior (1994).

Caputi et al. (2002) presented evidence, based on both in vivo and in vitro experiments, that the skipping of exon 51 that occurs with this mutation is due to the disruption of an SC35-dependent exonic splicing enhancer (ESE) within exon 51. In addition, this mutation induces nonsense-mediated decay (NMD), which degrades the normally spliced mRNA in the patient's cells. In contrast to NMD, nonsense-mediated alternative splicing (NAS) does not require translation and is therefore not affected by inhibitors of translation. Maquat (2002) noted that ESE sequences are present in constitutively and alternatively spliced exons, are distinct from the splice site sequences, and are required for efficient splicing of certain exons. Maquat (2002) compared NAS with NMD of mRNA.


.0009 MARFAN SYNDROME

FBN1, ASN2144SER
  
RCV000017893...

In a 20-year-old man with skeletal and cardiac features of Marfan syndrome (MFS; 154700) but no ocular manifestations, Hewett et al. (1993) found heterozygosity for an A-to-G transition at position 6431 that changed the AAT codon for asparagine-2144 to the serine codon AGT. The same clinical features and mutation were shared by the father and the only sib. Hewett et al. (1993) suggested that the asn2144-to-ser mutation probably affects only the calcium-binding activity of the EGF-like module rather than its overall structure. This in turn suggested that the arg1137-to-pro (134797.0001) and cysteine substitutions found in other Marfan syndrome cases may exert their effect on phenotypes through interference with calcium binding rather than by any other mechanism. This mutation was previously designated as ASN1246SER.


.0010 MARFAN SYNDROME

FBN1, ASN548ILE
  
RCV000017894...

In a patient with classic and severe Marfan syndrome (MFS; 154700), Dietz et al. (1993) demonstrated an N548I missense mutation by SSCP analysis. This mutation was previously designated ASN-351ILE.

Reinhardt et al. (2000) showed that the N548I and glu1073-to-lys (E1073K; 134797.0038) mutations render the polypeptide significantly more susceptible to proteolytic degradation by a variety of proteases as compared with their wildtype counterparts.


.0011 MARFAN SYNDROME

FBN1, ASP723ALA
  
RCV000017895...

In a patient with classic and severe Marfan syndrome (MFS; 154700), Dietz et al. (1993) demonstrated a D723A missense mutation by SSCP analysis. This mutation was previously designated as ASP-176ALA.


.0012 MASS SYNDROME

FBN1, 4-BP INS, NT5138
  
RCV000017896

In a patient with mitral valve prolapse, extreme dolichostenomelia, early myopia, and striae distensae but no specific features of Marfan syndrome, Dietz et al. (1993) found insertion of 4 nucleotides, TTCA, after nucleotide 5138 resulting in a frameshift. The abnormality was a tandem insertion and was detected by SSCP analysis. The aortic root dimension in this patient was at the upper limit of normal when standardized to body surface area. The patient's mother and brother had moderately tall stature (without long-bone overgrowth) and myopia or mitral valve prolapse, respectively, but no specific features of the Marfan syndrome. The disorder in the patient satisfies the characteristics of the MASS phenotype (604308) as described by Glesby and Pyeritz (1989). Studies in the family showed that the mutation was de novo in the proband. Dietz et al. (1993) demonstrated extreme reduction in the amount of mutant allele transcript compared to that from the wildtype allele as opposed to the findings in missense mutations. These data, taken in connection with the mild clinical manifestations associated with the nonsense mutations, support a dominant-negative mechanism for the pathogenesis of the Marfan syndrome resulting from missense mutations. Dietz et al. (1993) presented a figure (their Fig. 6) to illustrate how they thought the dominant-negative model explains either severe or mild clinical manifestations. This mutation was previously designated as 2444INS4.


.0013 MARFAN SYNDROME

FBN1, 83-BP DEL
  
RCV000017897...

By SSCP analysis, Dietz et al. (1993) found deletion of 83 bp (comprising exon 2) creating a frameshift and a premature TAG stop codon in exon 4 in a patient with classic and severe manifestations of Marfan syndrome (MFS; 154700) in the ocular, skeletal, and cardiovascular systems. The mutation was thought to be de novo. The deletion was the result of a G-to-A transition at position +1 resulting in skipping of the upstream exon. It is noteworthy that the deletion in this patient was associated with severe disease despite expression of only the extreme 5-prime sequence from the mutant allele. These data suggest that the amino terminal region of fibrillin is critical to microfibrillar assembly and, in isolation, can participate in a dominant-negative fashion with wildtype monomer.


.0014 MARFAN SYNDROME

FBN1, IVS54DS, G-C, +1, 123-BP DEL
  
RCV000017898

In a 4-generation kindred with Marfan syndrome (MFS; 154700), Godfrey et al. (1993) detected in affected members a deletion of 123 bp by RT-PCR amplification of fibrillin mRNA. The deletion corresponded to an exon (exon 54) encoding an epidermal growth factor-like motif. The deleted region began at position 6664. Examination of genomic DNA showed a G-to-C transversion at the +1 consensus donor splice site. In this family, genetic linkage analysis with fibrillin-specific markers had been used to establish the prenatal diagnosis at 11 weeks of gestation. In this same family, Rantamaki et al. (1995) made the prenatal diagnosis of Marfan syndrome by identification of the mutation in a chorionic villus sample.


.0015 ECTOPIA LENTIS 1, ISOLATED, AUTOSOMAL DOMINANT

FBN1, GLU2447LYS
  
RCV000017899...

Kainulainen et al. (1994) described an E2447K mutation in a British 4-generation family in which 3 living subjects suffered from dominantly inherited ectopia lentis (ECTOL1; 129600). It was stated that the phenotype also included 'some skeletal manifestations, but no symptoms at all in the cardiovascular system.' The mutation was detected in the DNA of all subjects with dislocated lenses, as well as in the DNA of 3 other members of the family with only skeletal manifestations of the disorder.

In a 4-generation family with predominant ectopia lentis and only mild skeletal features of the Marfan syndrome but no sign of cardiovascular abnormality, Lonnqvist et al. (1994) found a G-to-A transition at nucleotide 7339, resulting in the substitution of lysine for glutamic acid at codon 2447 (E2447K) of fibrillin cDNA. It appears that this is the same family as that reported by Kainulainen et al. (1994). This mutation was previously designated as GLU1549LYS.

Comeglio et al. (2007) analyzed the FBN1 gene in the family previously studied by Lonnqvist et al. (1994) and identified the E2447K mutation in a 51-year-old affected individual who exhibited major ocular and cardiovascular manifestations as well as minor skeletal involvement. In Table 1, Comeglio et al. (2007) designated this patient as having Marfan syndrome (MFS; 154700).


.0016 MARFAN SYNDROME, NEONATAL

FBN1, CYS1074ARG
  
RCV000017900

In a Swiss infant with a severe, neonatal form of Marfan syndrome (MFS; 154700) (Raghunath et al., 1993), Kainulainen et al. (1994) found a C1074R mutation in the FBN1 gene. As expected, neither of the parents carried the mutation. This mutation was previously designated as CYS176ARG.


.0017 MARFAN SYNDROME

FBN1, ARG2776TER
  
RCV000017901...

In a 57-year-old patient with Marfan syndrome (MFS; 154700) and her 27-year-old son, Hayward et al. (1994) found an arg2776-to-ter mutation predicted to result in premature termination of the FBN1 polypeptide chain by 96 amino acids. This mutation was previously designated as ARG1878TER.


.0018 MARFAN SYNDROME, ATYPICAL

FBN1, ARG122CYS
  
RCV000017902...

Stahl-Hallengren et al. (1994) described an unusual mutation in the FBN1 gene in a family with several members affected with an atypical form of Marfan syndrome (MFS; 154700). The proband was 21 years old when he was referred to a rheumatologist because of pain in the hands during motion and episodes of knee joint effusions. There were no joint deformities, no scoliosis, and no cardiac symptoms. He had had spherophakia and lens dislocation since childhood. In his family, 8 members had lens dislocation and 7 of these underwent echocardiography with particular attention to aortic root dimensions and valvular function. No sign of aortic root dilatation, mitral valve prolapse, or other kind of cardiac involvement was observed either on physical examination or on echocardiography and there was no history of sudden deaths in the family. One or several episodes of knee joint effusion with moderate pain had occurred in 5 individuals. These episodes may have been related to moderate physical activity. Physical examination did not reveal ongoing joint effusion or other signs of synovitis in any of the family members. Five of the individuals with ectopia lentis had flexion contractures of the fifth proximal interphalangeal joint, whereas none of the other family members had this. The upper segment/lower segment ratio of the affected individuals was within the range characteristic of the Marfan syndrome. Linkage analysis with an informative marker in the vicinity of the fibrillin locus on chromosome 15, namely G113, revealed a lod score of 2.4 with no recombinations between the disorder and the marker. By using an automated sequenator in the screening of specific regions of FBN1 cDNA prepared from the cultured fibroblasts of the one affected family member, Stahl-Hallengren et al. (1994) identified a C-to-T transition at nucleotide 364. This mutation substituted a cysteine for arginine-122 (R122C). The mutation was confirmed in genomic DNA of the proband by use of the solid-phase minisequencing technique. This technique was also used to establish that all affected members of the family carried the same mutation, whereas unaffected members did not have the mutation. Furthermore, none of 60 Marfan patients or 60 healthy controls analyzed was shown to carry this mutation. The fibrillin polypeptide is made up of 47 repetitive EGF-like repeats interspersed by other motifs. Most of the EGF-like motifs have calcium-binding properties; however, 3 of them located close to the amino-terminal end of the fibrillin polypeptide exhibit the characteristic 6-cysteine pattern, but lack the putative calcium-binding consensus sequence. The R122C mutation in this family occurred in the second of these 3 non-calcium-binding EGF-like motifs and resulted in an extra cysteine just before the conserved second cysteine in this motif. Stevenson et al. (1982) gave the clinical description of 2 families with ectopia lentis in association with dolichostenomelia and joint stiffness.


.0019 MARFAN SYNDROME, NEONATAL

FBN1, IVS31AS, A-T, -2
  
RCV000017903

In a patient with the severe neonatal form of Marfan syndrome (MFS; 154700) leading to death at 3 months of age due to cardiac and respiratory failure, Wang et al. (1995) found missplicing of exon 31 of the FBN1 gene due to an A-to-T transversion at the -2 position of the consensus acceptor splice site. Exon 31 encodes an EGF-like calcium binding domain. This was a de novo mutation case; the father was 37 years old.


.0020 MARFAN SYNDROME, NEONATAL

FBN1, IVS32DS, G-A, +1
  
RCV000017904...

Wang et al. (1995) found a missplicing mutation of exon 32 in a female infant with severe neonatal Marfan syndrome (MFS; 154700). The infant died at 5 months of age due to cardiac failure. A G-to-A transition at the +1 position of the donor splice site of intron 32 was identified. The patient represented a new mutation.


.0021 MARFAN SYNDROME, MILD

FBN1, GLY1127SER
  
RCV000017905...

Francke et al. (1995) identified disease of the ascending aorta, ranging from mild aortic root enlargement to aneurysm and/or dissection, in 10 individuals of a kindred, none of whom had classic Marfan syndrome (MFS; 154700). The proband was a 72-year-old woman, 174.5 cm tall, who was referred because of aortic root aneurysm, aortic regurgitation, and mitral valve prolapse. A brother had been discovered to have a type A aortic dissection with normal aortic valve and normal sinus of Valsalva at the age of 65 and successful surgical repair was performed. Single-strand conformation analysis of the entire FBN1 cDNA of an affected family member demonstrated a G-to-A transition at nucleotide 3379, predicting a gly1127-to-ser substitution. The glycine in this position is highly conserved in EGF-like domains of FBN1 and other proteins. The mutation was present in 9 of 10 affected family members and in 1 young unaffected member, but was not found in other unaffected members, in 168 chromosomes from normal controls, or in 188 chromosomes from other individuals with Marfan syndrome or related phenotypes. FBN1 intragenic marker haplotypes ruled out the possibility that the other allele played a significant role in modulating the phenotype in this family. Pulse-chase studies revealed normal fibrillin synthesis but reduced fibrillin deposition into the extracellular matrix in cultured fibroblasts from a gly1127-to-ser carrier. Francke et al. (1995) suggested that mutations such as this may disrupt EGF-like domain folding less dramatically than do substitutions of cysteine or other amino acids important for calcium-binding that cause classic Marfan syndrome. They suggested that the findings in this family were consistent with an emerging recognition that FBN1 alterations produce a spectrum of connective tissue disorders that extend beyond the classic Marfan phenotype and for which the term fibrillinopathy has been proposed.


.0022 MARFAN SYNDROME

FBN1, CYS1223TYR
  
RCV000017906...

Hewett et al. (1994) described a patient with Marfan syndrome (MFS; 154700) who was heterozygous for a G-to-A transition at nucleotide 3952 in the FBN1 gene that resulted in a cys1223-to-tyr (C1223Y) substitution.

In a 7-year-old girl with typical ocular, skeletal, and cardiovascular features of Marfan syndrome but with additional features suggesting the diagnosis of Shprintzen-Goldberg syndrome (SGS; 182212), including hypotonia, scaphocephaly with craniosynostosis, low-set anomalous ears, hyperelastic skin, diastasis recti, vertical talus, and mental retardation, Dietz et al. (1995) found a G-to-A transition at nucleotide 3668, resulting in a C1223Y substitution within one of the repetitive EGF-like domains within fibrillin-1. The mutation occurred as a de novo event in heterozygous state and was not detected in over 100 chromosomes from control individuals. Although cysteine substitutions in EGF-like domains represent the most common class of mutations causing Marfan syndrome, no mutation causing Marfan syndrome had been found in the specific domain harboring C1223Y. The demonstration that fibrillin-1 is expressed as early as the 8-cell stage of human development was considered consistent with a possible role for fibrillin-1 in early craniofacial and CNS development. See Sood et al. (1996) for further details. Also see 134797.0045 for another patient with features of both disorders.


.0023 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

FBN1, ARG2726TRP
  
RCV000029787...

This variant, formerly titled MARFANOID SKELETAL SYNDROME, has been reclassified based on the findings of Buoni et al. (2004) and Van Dijk et al. (2009).

Milewicz et al. (1995) demonstrated a profibrillin processing mutation in a 13-year-old boy with isolated skeletal features of the Marfan syndrome. He was 6 feet tall (more than 95th percentile for age) with upper-to-lower segment ratio of 0.89 and with pectus carinatum, scoliosis, arachnodactyly, and pes planus. Echocardiogram and eye examination were normal. Only one-half of the secreted profibrillin was proteolytically processed to fibrillin outside the cell and deposited in the extracellular matrix. Electron microscopic examination showed that rotary shadowed microfibrils made by the proband's fibroblasts were indistinguishable from control cells. Sequencing of the FBN1 gene demonstrated a heterozygous C-to-T transition at nucleotide 8176, resulting in the substitution of tryptophan for arginine (R2726W) at a site immediately adjacent to a consensus sequence recognized by a cellular protease. Six other individuals in the proband's family had the FBN1 mutation that segregated with tall stature. None of the affected individuals had cardiac or ocular manifestations of the Marfan syndrome. This mutation identified a putative site for profibrillin-to-fibrillin processing and was associated with isolated skeletal features of the Marfan syndrome, indicating to the authors that the FBN1 gene is one of the genes that determine height in the general population. The authors stated that the cellular effect of the mutation may be equivalent to a 'null' FBN1 mutation and is consistent with the mild phenotype associated with null alleles as opposed to the dominant-negative effect with severe phenotype observed with missense mutations.

Buoni et al. (2004) described the same R2726W mutation of FBN1 in an 18-year-old man and his 41-year-old mother. Both were of average height. The son had scoliosis, pectus carinatum, pes planus, arachnodactyly, and normal upper/lower segment ratio and arm span to height.

Van Dijk et al. (2009) reported the R2726W mutation in exon 64 of the FBN1 gene in phenotypically normal father and son. The mother and a second son had classic features of Marfan syndrome; she was heterozygous for a cysteine substitution in FBN1 (C1928S) and the son was compound heterozygous for the C1928S and the R2726W mutations. Van Dijk et al. (2009) stated that the son was more severely affected than his mother; he underwent aortic root surgery at a younger age (19 years with a measurement of 48 mm vs 35 years with a measurement of 60 mm), was treated for a type B aortic dissection at age 21 years, and had more skeletal features of MFS than his mother. This mutation may be associated with incomplete penetrance and may have no effect or only mild skeletal manifestations.


.0024 REMOVED FROM DATABASE


.0025 MARFAN SYNDROME

FBN1, CYS1117TYR
  
RCV000017890...

In a patient with Marfan syndrome (MFS; 154700), Tynan et al. (1993) identified a G-to-A change at nucleotide 3350 of the FBN1 gene, resulting in a cys1117-to-tyr substitution.


.0026 MARFAN SYNDROME

FBN1, CYS1242TYR
  
RCV000017891...

In a patient with Marfan syndrome (MFS; 154700), Kainulainen et al. (1994) identified a G-to-A change at nucleotide 3725 of the FBN1 gene, resulting in a cys1242-to-tyr substitution.


.0027 MARFAN SYNDROME, NEONATAL

FBN1, LYS1043ARG
  
RCV000017909...

Wang et al. (1997) described 3 FBN1 mutations. Two of them were in patients with the neonatal form of Marfan syndrome (MFS; 154700); the third was in a patient with classic Marfan syndrome. All 3 occurred in the same region that had been found to harbor neonatal Marfan syndrome mutations. The first patient had striking skeletal features of Marfan syndrome, including soft, loose skin, crumpled ears, and joint contractures at birth. Eye and cardiac examinations were normal. At 7 months of age, he developed an aggressive scoliosis; however, his contractures were no longer evident. Hypotonia and marked mitral valve prolapse (which had not been evident at birth) were noted. At 14 months of age, an extensive mitral valve repair was performed. Postoperative complications necessitated replacement with a St. Jude mechanical prosthesis 3 weeks later and a porcine heterograft 2 months after the initial valve repair. At 20 months of age, he underwent plication of the right hemidiaphragm and resection of the bulbous cysts of the left lung. The patient died suddenly at 2 years of age. Diffuse changes of the Marfan syndrome were found in the vessels and emphysematous changes in the lungs at autopsy were noted. Amplified genomic DNA from the patient using intron primers to exon 25 showed heteroduplex formation when run on mutation detection enhancement (MDE) gels. Sequence analysis showed an A-to-G transition at position 3128 that caused a lysine-to-arginine substitution at amino acid position 1043 (K1043R) in 1 allele.


.0028 MARFAN SYNDROME, NEONATAL

FBN1, ASN1131TYR
  
RCV000017910

In a patient with the neonatal form of Marfan syndrome (MFS; 154700), Wang et al. (1997) described an A-to-T transversion at position 3391 in the FBN1 gene that caused an asparagine-to-tyrosine substitution at amino acid position 1131 (N1131Y).


.0029 MARFAN SYNDROME

FBN1, 1-BP DEL, 3192A
  
RCV000017911

In a patient considered to have classic Marfan syndrome (MFS; 154700), Wang et al. (1997) used amplified genomic DNA and intron primers to exon 25 to demonstrate heteroduplex formation on mutation detection enhancement (MDE) gels. Sequence analysis showed a 1-bp deletion (A) at position 3192 in exon 25. This caused a frameshift and premature stop that would predict synthesis of a truncated protein of 1,086 amino acids. The change was not observed in either clinically unaffected parents and thus represented a de novo mutation. The patient was born with pectus excavatum that was repaired at age 13 years of age. He had mild scoliosis that required no treatment. When he was 20 years old, the question of Marfan syndrome was raised on the basis of his marfanoid habitus with upper-to-lower segment ratio of 0.88, high-arched palate, arachnodactyly, positive thumb and wrist signs, and mild hyperextensibility. Ophthalmologic examination was normal. Echocardiography showed mild aortic root dilation without valvular insufficiency. There was no evidence of mitral valve prolapse. He was treated with a beta-blocker. Echocardiogram 3 years later showed mild aortic insufficiency, normal left ventricular function, and aortic root diameter 4.2 cm, and again no mitral involvement. Wang et al. (1997) marveled at the fact that the mutation in this relatively mild, although classic, case of Marfan syndrome occurred in the same region as the mutations in 2 cases of neonatal Marfan syndrome (134797.0027, 134797.0028).


.0030 MARFAN SYNDROME

FBN1, 6354C-T, EX51DEL, ILE2118ILE
  
RCV000017912...

Liu et al. (1997) carried out a systematic mutation search of PCR-amplified transcripts of the FBN1 gene from patients with Marfan syndrome (MFS; 154700). By long RT-PCR and restriction enzyme digestions, they identified skipping of FBN1 exons in 10% of Marfan cases. All but 1 of these were due to sequence alterations at splice sites. In skin fibroblasts derived from a patient with classic Marfan syndrome, an abnormally migrating restriction fragment was identified and found to represent deletion of 66 bp due to in-frame skipping of the entire exon 51. This exon encodes the 3-prime portion of 1 of the 7 8-cysteine domains in FBN1 that is similar to a motif found in transforming growth factor-beta-1 binding protein (150390). Sequencing of exon 51 and surrounding splice sites, amplified from genomic DNA with intron primers, identified only 1 sequence variation unique to this sample: a C-to-T transition (6354C-T) at position +41 of exon 51. This mutation changes codon 2118 from AUC to AUU, both of which encode isoleucine. Liu et al. (1997) stated that this nucleotide change is unlikely to affect known binding sites of the splicing machinery. Further studies indicated that the skipping of exon 51 in these cells was due solely to the silent mutation, 6354C-T. Skipping of exon 51 associated with a 6339T-G mutation that changes a tyrosine (TAT) to a termination (TAG) codon (134797.0008) was previously reported as the cause of exon 51 skipping (Dietz et al., 1993; Dietz and Kendzior, 1994). Liu et al. (1997) commented that skipping caused by a silent mutation suggests the existence of an alternative mechanism of exon skipping yet to be discovered.


.0031 MARFAN SYNDROME, CLASSIC

FBN1, CYS1265ARG
  
RCV000017913

Montgomery et al. (1998) found a T-to-C transition at nucleotide 3793 of the FBN1 gene, predicting the substitution of arginine for cysteine at codon 1265, within a calcium-binding epidermal growth factor-like domain of fibrillin-1 in a mother and son who fulfilled criteria for Marfan syndrome (MFS; 154700); 2 other sons of the woman seemed to have the Marfan syndrome, although in milder form. Haplotype analysis using 4 intragenic microsatellite polymorphic markers showed, however, that these 2 children could have not inherited the Marfan mutation, and indeed the mutation was not demonstrated in these children.


.0032 MASS SYNDROME

FBN1, ARG1170HIS
  
RCV000148494...

Montgomery et al. (1998) described a G-to-A transition at nucleotide 3509 of the FBN1 coding sequence, predicted to result in the substitution of histidine for arginine at codon 1171, within a calcium-binding EGF-like domain of the protein. The clinical manifestations in several members of the family were suggestive of Marfan syndrome (154700) but did not satisfy the revised diagnostic criteria presented by De Paepe et al. (1996). Thus the disorder in this family was considered to be a subdiagnostic variant of Marfan syndrome; see MASS syndrome (604308). The proband, 46 years of age at the time of report, was diagnosed with a nonspecific connective tissue disorder because dolichostenomelia, joint hypermobility, kyphoscoliosis, pes planus, positive wrist and thumb signs, striae distensae, early myopia, and myxomatous mitral leaflets with mitral valve prolapse were found. There was no lens dislocation, and all aortic measurements were within normal limits when standardized to age and body surface area. Multiple family members, including all 4 of the proband's children and her brother, father, and paternal uncle, had a tall, thin body habitus and/or preadolescent myopia. Two individuals, the proband's father and eldest son, also showed more specific findings, including arachnodactyly, dolichostenomelia, pectus deformity, scoliosis, positive wrist and thumb signs, and mitral valve prolapse. Like the proband, neither of these individuals had lens dislocation or aortic dilatation.


.0033 MARFAN SYNDROME

FBN1, ARG529TER
  
RCV000017915...

In a patient with Marfan syndrome (MFS; 154700), Montgomery et al. (1998) found a C-to-T transition at nucleotide 1585 of the fibrillin-1 coding sequence, predicting substitution of a premature termination codon for arginine at codon 529, within a calcium-binding EGF-like domain of fibrillin-1. The diagnosis of Marfan syndrome was made in the patient at the age of 24 years when an echocardiogram showed dilatation of the aortic root to 8 cm and chronic dissection of the ascending aorta. Associated features included preadolescent myopia, dolichostenomelia, asymmetric pectus carinatum, scoliosis, joint hypermobility, pes planus, and widespread striae distensae. There was no lens dislocation. The proband's mother, 60 years of age at the time of report, showed only joint hypermobility, pes planus, and striae distensae of the abdomen and trunk. There was no myopia or lens dislocation, and all aortic measurements were within normal limits when standardized to age and body surface area. The mother was found to be mosaic for the arg529-to-ter mutation. The mutation was thought to be present in approximately 43% of lymphoblasts and in 51% of fibroblasts.


.0034 MARFAN SYNDROME, ATYPICAL

FBN1, GLY985GLU
  
RCV000017916...

In a family with an atypical form of Marfan syndrome (MFS; 154700), Collod-Beroud et al. (1999) demonstrated germline mosaicism for a gly985-to-glu (G985E) mutation of the FBN1 gene. The proband was a 16-year-old boy with dilation of the ascending aorta (46 mm at the sinuses of Valsalva, 8 SD above the mean when standardized to age and body surface area), mitral valve prolapse with regurgitation, highly arched palate, arachnodactyly (positive wrist and thumb signs), tall stature (199 cm, +4 SD, 76 kg), and scoliosis. His 9-year-old brother displayed dilation of the ascending aorta (32 mm at the sinuses of Valsalva, 6 SD above the mean when standardized to age and body surface area), arachnodactyly (positive wrist and thumb signs), dolichostenomelia (arm span-to-height ratio, 1.05), tall stature (144 cm, +3 SD, 31 kg), highly arched palate, and joint hypermobility. No other anomalies typical of MFS (including ectopia lentis) were found in either subject. Both parents had no sign suggesting MFS, and another brother was unaffected. The G985E substitution was present in heterozygous state and resulted from a G-to-A transition at nucleotide 2954. Several lines of evidence indicated that this was the disease-causing mutation: the mutation was not observed during screening of 306 chromosomes; the mutation substitutes an uncharged or negatively charged amino acid much higher in molecular weight; and the mutational event occurred in the 8-cysteine module 3 at a position conserved in bovine, murine, and porcine sequences. The G985E mutation created a new TaqI restriction site, resulting in 2 fragments of 202 and 217 bp by which the mutation could be sought in members of the family. The 217-bp fragment resulting from digestion was found at a very low level in the father's white blood cell DNA, but was not found in that from the mother or in controls. Careful reassessment of the clinical examination of the father (performed systematically before the identification of the mosaicism) revealed no skeletal or ocular sign but minor findings: discrete dilation of the ascending aorta (43 mm, +2 SD when standardized to age and body surface area (193 cm, 75 kg, at age 41 years)) and minimal aortic regurgitation. Collod-Beroud et al. (1999) commented that the G985E mutation, which occurred in exon 24, was not associated with ocular anomalies. This was of interest because study of the Marfan database (Collod-Beroud et al., 1998) indicated that half (9 of 19) of the mutations not associated with ocular anomaly were located in exons 23 to 29. This contrasted with mutations associated with a complete classic MFS phenotype, which were widely distributed throughout the gene.


.0035 MARFAN SYNDROME

FBN1, IVS2DS, G-A, +1
  
RCV000035141...

In a Japanese patient with Marfan Syndrome, Chikumi et al. (2000) identified a recurrent de novo mutation, IVS2DS+1G-A. This mutation had been identified in a sporadic case by Dietz et al. (1993), who found that it resulted in a skipping of exon 2.


.0036 MARFAN SYNDROME

FBN1, GLY1013ARG
  
RCV000017918

In 2 unrelated patients with atypically severe, early-onset manifestations of Marfan syndrome (MFS; 154700), Tiecke et al. (2001) identified a G-to-A transition at nucleotide 3037 in exon 24 of the FBN1 gene, resulting in a gly1013-to-arg (G1013R) substitution. In both cases the mutation was ruled out in the clinically unaffected parents. The G1013R mutation affects a highly conserved residue in the interdomain linkage region, which may play a role in interdomain flexibility. The mutation was first reported by Nijbroek et al. (1995) in a patient with atypically severe manifestations and it therefore represents a recurrent mutation. Tiecke et al. (2001) identified the G1013R mutation by heteroduplex screening in a fourth unrelated patient with severe clinical involvement, who was not a member of their initial screening group.


.0037 MARFAN SYNDROME

FBN1, 33-BP INS, IVS46, G-A, +1
  
RCV000017919

Hutchinson et al. (2001) studied a patient with Marfan syndrome (MFS; 154700) whose mutation was not detected by heteroduplex analysis. Primary cultured patient fibroblasts were metabolically labeled and found to secrete fibrillin-1 defectively when compared with an age-matched control. Sequencing of patient cDNA, isolated by RT-PCR of patient fibroblast RNA, detected a 33-bp insertion. The reading frame of the mutant allele was maintained and predicted the insertion of 11 amino acids at the beginning of calcium-binding epidermal growth factor-like domain 29. Direct sequencing of genomic DNA detected a heterozygous G-to-A transversion at the +1 position of intron 46 of the FBN1 gene. The 11-amino acid insertion was a consequence of the usage of a cryptic splice site 33 bp downstream of the mutation. This was the first reported case of a splicing defect in FBN1 leading to the production of a full length fibrillin-1 transcript containing a large amino acid insertion. The patient represented a sporadic case of Marfan syndrome. At the age of 27 years he showed skeletal features including pectus excavatum, an arm span-to-height ratio of 1.09, arachnodactyly, kyphoscoliosis, highly arched palate with dental crowding, and typical facial appearance (downslanting palpebral fissures, enophthalmos, and malar hypoplasia). He had bilateral ectopia lentis and underwent aortic root replacement at the age of 23 years.


.0038 MARFAN SYNDROME, NEONATAL

FBN1, GLU1073LYS
  
RCV000017920...

The glu1073-to-lys (E1073K) mutation in FBN1, found in a patient with Marfan syndrome of the severe neonatal form (MFS; 154700), was used by Reinhardt et al. (2000) to demonstrate that mutations in calcium-binding epidermal growth factor modules render fibrillin-1 susceptible to proteolysis.

The same mutation was found by Ades et al. (2006) in a patient with arachnodactyly noted at birth and with ophthalmologic findings at age 5 months that included bilateral lens dislocation.


.0039 MARFAN SYNDROME

FBN1, IVS46+5G-A
  
RCV000035236...

In patients with Marfan syndrome (MFS; 154700), Nijbroek et al. (1995) and Liu et al. (1996) reported skipping of exon 46 of the FBN1 gene due to a G-to-A transition at the +5 position of the consensus 5-prime splice site. Collod-Beroud et al. (2003) noted that this mutation was the most frequently recurring mutation to that time, having been reported a total of 9 times.


.0040 WEILL-MARCHESANI SYNDROME 2

FBN1, 24-BP DEL
  
RCV000017922

In affected members of a family with autosomal dominant Weill-Marchesani syndrome (WMS2; 608328) first reported by Gorlin et al. (1974), Faivre et al. (2003) identified heterozygosity for a 24-bp in-frame deletion (5074del24) in exon 41 of the FBN1 gene. The mutation cosegregated with disease and was not found in 186 controls.


.0041 MARFAN SYNDROME

FBN1, TYR754CYS
  
RCV000017923...

In a family of Australian Aboriginal/European background extensively affected with Marfan syndrome (MFS; 154700), Summers et al. (2004) identified a 2262A-G transition in the FBN1 gene, resulting in a tyr754-to-cys (Y754C) mutation. The addition or removal of cysteine in the calcium-binding EGF domains of fibrillin had consistently been associated with Marfan syndrome, supporting the pathogenic nature of the mutation. Furthermore, the mutation affects a conserved tyrosine that is involved in the interaction between adjacent EGF domains.


.0042 MARFAN SYNDROME

ECTOPIA LENTIS 1, ISOLATED, AUTOSOMAL DOMINANT, INCLUDED
FBN1, ARG240CYS
  
RCV000017924...

Edwards et al. (1994) described a large kindred with ectopia lentis (ECTOL1; 129600) showing linkage to FBN1. Ades et al. (2004) provided follow-up data on the family and demonstrated an arg240-to-cys (R240C) mutation in the FBN1 gene. The same mutation had been reported 3 times previously: once in a family with classic Marfan syndrome (MFS; 154700), including a 31-year-old patient with major skeletal, ocular, and cardiovascular manifestations (Loeys et al., 2001); once in 1 member of a multigenerational ectopia lentis kindred (Korkko et al., 2002); and once in an adult from a familial ectopia lentis kindred who had ectopia lentis and involvement of the integument, without cardiovascular involvement (Comeglio et al., 2002).

Faivre et al. (2007) found that a missense mutation substituting or producing cysteine was associated with a high probability of ectopia lentis when compared with other missense mutations.


.0043 MARFAN SYNDROME, NEONATAL

FBN1, CYS1032TYR
  
RCV000017926...

In a male infant with the neonatal form of Marfan syndrome (MFS; 154700) leading to death at the age of 4 months, Elcioglu et al. (2004) identified a heterozygous 3095G-A transition in exon 25 of the FBN1 gene, resulting in a cys1032-to-tyr (C1032Y) substitution. The infant had severe arachnodactyly, hypermobility of the fingers, flexion contractures of elbows, wrists, hips, and knees, microretrognathia, crumpled ears, 'rocker-bottom' feet, loose redundant skin, and lens dislocations. The cause of death was cardiac failure from cardiac valve insufficiency and aortic dilatation.


.0044 MARFAN SYNDROME

FBN1, CYS1129TYR
  
RCV000017927...

In a sporadic case of Marfan syndrome, El-Aleem et al. (1999) identified a 3386G-A transition in the FBN1 gene, resulting in a cys1129-to-tyr (C1129Y) substitution.


.0045 MARFAN SYNDROME

FBN1, CYS1221TYR
  
RCV000030943

In a Japanese boy with Marfan syndrome (MFS; 154700) who also had features of Shprintzen-Goldberg syndrome (182212), including craniosynostosis and mental retardation, Kosaki et al. (2006) identified heterozygosity for a 3662G-A transition in the FBN1 gene, resulting in a cys1221-to-tyr (C1221Y) substitution in an EGF-like domain. The boy had pectus carinatum, scoliosis, arachnodactyly with contractures of the interphalangeal joints, pes planus, and dolichocephaly. An echocardiogram demonstrated minimal enlargement of the aortic root and mitral valve prolapse with mild tricuspid insufficiency. Also see 134797.0022 for another patient with features of both disorders.


.0046 MARFAN SYNDROME, NEONATAL

FBN1, CYS1086TYR
  
RCV000017929

In a male infant with severe neonatal Marfan syndrome (MFS; 154700), Tekin et al. (2007) identified a heterozygous 3257G-A transition in exon 25 of the FBN1 gene, resulting in a cys1086-to-tyr (C1086Y) substitution in the EGF-like domain. Two older brothers were similarly affected, and all 3 sibs died at ages 2 to 4 months of cardiorespiratory insufficiency. Mosaicism for the mutation was identified in somatic cells and germ cells of the clinically unaffected father. Tekin et al. (2007) stated that this was the first report of familial neonatal Marfan syndrome.


.0047 MARFAN SYNDROME, AUTOSOMAL RECESSIVE

FBN1, ARG485CYS
  
RCV000017930...

In 2 cousins with Marfan syndrome (MFS; 154700) in a consanguineous Turkish family, de Vries et al. (2007) identified homozygosity for a 1453C-T transition in exon 11 of the FBN1 gene, resulting in an arg485-to-cys (R485C) substitution. All 4 healthy parents were heterozygous for the mutation and none fulfilled the Ghent criteria for Marfan syndrome. The mutation is located in a calcium-binding EGF-like domain and was not found in 500 control chromosomes.


.0048 MARFAN SYNDROME

FBN1, 302.5-KB DEL
   RCV000017931

In a patient with Marfan syndrome (MFS; 154700) in whom no mutation was detected by standard genetic testing, Matyas et al. (2007) used multiplex ligation-dependent probe analysis (MLPA) and high-density SNP arrays to analyze the FBN1 gene and identified a 302,580-bp deletion, involving the putative regulatory and promoter regions of FBN1 as well as a neighboring gene, CEP152 (613529). Sequence analysis of RT-PCR products revealed transcripts from only 1 allele, indicating true haploinsufficiency.


.0049 MARFAN SYNDROME

FBN1, EX13-49DEL
   RCV000017932

In a girl with severe early-onset Marfan syndrome (MFS; 154700), Blyth et al. (2008) identified somatic mosaicism for a heterozygous deletion of exons 13 through 49 of the FBN1 gene in both peripheral blood and saliva. She was diagnosed at age 3 years due to subluxation of the lenses, marked myopia, ligamentous laxity and valgus ankles. Echocardiogram at age 3 showed dilation of the aortic root to the upper limits of normal and mild tricuspid regurgitation. Other features apparent by age 4 included joint hypermobility, scoliosis, arachnodactyly, high-arched palate, and thin, long face. Blyth et al. (2008) suggested that Marfan patients with FBN1 deletions have a more severe phenotype.


.0050 STIFF SKIN SYNDROME

FBN1, TRP1570CYS, 4710G-T
  
RCV000017933

In affected members of a 5-generation family segregating autosomal dominant stiff skin syndrome (184900), Loeys et al. (2010) identified heterozygosity for a 4710G-T transversion in exon 37 of the FBN1 gene, resulting in a trp1570-to-cys (W1570C) substitution at a key structural residue in the N-terminal portion of the fourth TGF-beta (190180)-binding protein-like domain (N-TB4). The mutation was not found in more than 400 ethnically matched control chromosomes.

In transiently transfected HEK293 cells and in the MSU-1.1 human fibroblast cell line, Jensen et al. (2015) demonstrated that the W1570C mutant is secreted into the extracellular media and incorporates into the microfibril network.


.0051 STIFF SKIN SYNDROME

FBN1, TRP1570CYS, 4710G-C
  
RCV000017934

In 3 affected members of a family segregating autosomal dominant stiff skin syndrome (184900), Loeys et al. (2010) identified heterozygosity for a 4710G-C transversion in exon 37 of the FBN1 gene, resulting in a trp1570-to-cys (W1570C) substitution at a key structural residue in the N-terminal portion of the TB4 domain. The mutation was not found in more than 400 ethnically matched control chromosomes.

In transiently transfected HEK293 cells and in the MSU-1.1 human fibroblast cell line, Jensen et al. (2015) demonstrated that the W1570C mutant is secreted into the extracellular media and incorporates into the microfibril network.


.0052 STIFF SKIN SYNDROME

FBN1, CYS1564SER
  
RCV000017935

In 3 affected members of a family segregating autosomal dominant stiff skin syndrome (184900), Loeys et al. (2010) identified heterozygosity for a 4691G-C transversion in exon 37 of the FBN1 gene, resulting in a cys1564-to-ser (C1564S) substitution at an evolutionarily conserved residue in the N-terminal portion of the TB4 domain. The mutation was not found in more than 400 ethnically matched control chromosomes.

In transiently transfected HEK293 cells and in the MSU-1.1 human fibroblast cell line, Jensen et al. (2015) demonstrated that the C1564S mutant is secreted into the extracellular media and incorporates into the microfibril network.


.0053 STIFF SKIN SYNDROME

FBN1, CYS1577GLY
  
RCV000017936

In a 54-year-old man with stiff skin syndrome (184900), Loeys et al. (2010) identified heterozygosity for a 4729T-G transversion in exon 37 of the FBN1 gene, resulting in a cys1577-to-gly (C1577G) substitution at an evolutionarily conserved residue in the N-terminal portion of the TB4 domain. The mutation was not found in more than 400 ethnically matched control chromosomes.


.0054 STIFF SKIN SYNDROME

FBN1, GLY1594ASP
  
RCV000017937...

In a 14-year-old boy with stiff skin syndrome (184900) associated with ectopia lentis, Loeys et al. (2010) identified heterozygosity for a de novo 4781G-A transition in exon 38 of the FBN1 gene, resulting in a gly1594-to-asn (G1594N) substitution in the C-terminal portion of the TB4 domain (C-TB4). The mutation was not found in more than 400 ethnically matched control chromosomes. This mutation was erroneously published as GLY1594ASN; Dietz (2014) confirmed that the correct substitution is GLY1594ASP.


.0055 GELEOPHYSIC DYSPLASIA 2

ACROMICRIC DYSPLASIA, INCLUDED
FBN1, TYR1699CYS
  
RCV000022543...

In 5 patients with geleophysic dysplasia-2 (GPHYSD2; 614185) and 1 with acromicric dysplasia (ACMICD; 102370), Le Goff et al. (2011) identified heterozygosity for a 5096A-G transition in the FBN1 gene, resulting in a tyr1699-to-cys (Y1699C) substitution within the TGFB (190180)-binding protein-like 5 (TB5) domain. The mutation was not found in 2,000 ethnically matched controls or in the Marfan mutation database.


.0056 GELEOPHYSIC DYSPLASIA 2

FBN1, GLY1762SER
  
RCV000022545...

In 6 patients with geleophysic dysplasia-2 (GPHYSD2; 614185), Le Goff et al. (2011) identified heterozygosity for a 5284G-A transition in the FBN1 gene, resulting in a gly1762-to-ser (G1762S) substitution within the TB5 domain. The mutation was not found in 2,000 ethnically matched controls or in the Marfan mutation database.

In transiently transfected HEK293 cells and in the MSU-1.1 human fibroblast cell line, Jensen et al. (2015) demonstrated that the G1762S mutant is secreted into the extracellular media and incorporates into the microfibril network.


.0057 GELEOPHYSIC DYSPLASIA 2

ACROMICRIC DYSPLASIA, INCLUDED
FBN1, ALA1728THR
  
RCV000022546...

In 1 patient with geleophysic dysplasia-2 (GPHYSD2; 614185) and 1 with acromicric dysplasia (ACMICD; 102370), Le Goff et al. (2011) identified heterozygosity for a 5182G-A transition in the FBN1 gene, resulting in an ala1728-to-thr (A1728T) substitution within the TB5 domain. The mutation, which was de novo in both patients, was not found in 2,000 ethnically matched controls or in the Marfan mutation database.


.0058 GELEOPHYSIC DYSPLASIA 2

FBN1, TYR1696CYS
  
RCV000022548...

In 2 unrelated patients with geleophysic dysplasia-2 (GPHYSD2; 614185), both of whom died in the first decade of life, Le Goff et al. (2011) identified heterozygosity for a 5087A-G transition in the FBN1 gene, resulting in a tyr1696-to-cys (Y1696C) substitution within the TB5 domain. One patient was Belgian and had mitral stenosis and insufficiency, underwent tracheotomy at age 3 years, and died at 9 years of age. The other patient, who was from the U.K. and had respiratory insufficiency, pulmonary artery hypertension, and sleep apnea, died at 3 years of age. The mutation, which was de novo in both patients, was not found in 2,000 ethnically matched controls or in the Marfan mutation database.


.0059 ACROMICRIC DYSPLASIA

FBN1, SER1750ARG
  
RCV000022549...

In a French mother and 2 children with acromicric dysplasia (ACMICD; 102370), Le Goff et al. (2011) identified heterozygosity for a 5251T-G transversion in the FBN1 gene, resulting in a ser1750-to-arg (S1750R) substitution within the TB5 domain. The mutation was not found in 2,000 ethnically matched controls or in the Marfan mutation database.


.0060 ACROMICRIC DYSPLASIA

FBN1, TYR1700CYS
  
RCV000022550...

In a Chinese mother and child with acromicric dysplasia (ACMICD; 102370), Le Goff et al. (2011) identified heterozygosity for a 5099A-G transition in the FBN1 gene, resulting in a tyr1700-to-cys (Y1700C) substitution within the TB5 domain. The mutation was not found in 2,000 ethnically matched controls or in the Marfan mutation database.

In transiently transfected HEK293 cells and in the MSU-1.1 human fibroblast cell line, Jensen et al. (2015) demonstrated that the Y1700C mutant is secreted into the extracellular media and incorporates into the microfibril network.


.0061 ACROMICRIC DYSPLASIA

FBN1, 3-BP DUP, NT5202
  
RCV000022551

In a French patient with acromicric dysplasia (ACMICD; 102370), Le Goff et al. (2011) identified heterozygosity for a 3-bp duplication at nucleotide 5202 in the FBN1 gene, resulting in duplication of a glutamine at codon 1735 (gln1735dup) within the TB5 domain. The mutation was not found in 2,000 ethnically matched controls or in the Marfan mutation database.


.0062 FNB1 POLYMORPHISM

FBN1, PRO1148ALA
  
RCV000029726...

Dietz et al. (1995) reported an 11-year-old girl with typical features of Marfan syndrome who also had hypotonia, scaphocephaly with craniosynostosis, ocular proptosis, low-set anomalous ears, micrognathia, hyperelastic skin, umbilical hernia, talipes equinovarus, and mental retardation. In this patient, Dietz et al. (1995) identified a C-to-G transversion at nucleotide 3442, substituting alanine for proline at codon 1148 (P1148A) within an EGF-like domain. This mutation was not present in the mother; the father's DNA was not available for study. The same mutation had been found in apparently unaffected members of families with Marfan syndrome or an isolated aortic aneurysm and had been found with much higher frequency in families affected by Marfan syndrome than in controls (Tynan et al., 1993). Indeed, Dietz et al. (1995) had identified P1148A in approximately 5% of the affected families, but in none of over 300 chromosomes from a control population. This suggested that P1148A defines a predisposing allele that is subject to extreme modification by epistatic, stochastic, and/or environmental modifiers. Sood et al. (1996) reported further on these 2 patients. Schrijver et al. (1997) screened 416 unrelated control individuals for the P1148A substitution and found an allele frequency of 3.8%. They observed a similar allele frequency (3%) after screening 133 patients with connective tissue disorders, including 55 with Marfan syndrome and 54 with aortic aneurysms. The authors concluded that the P1148A substitution is a polymorphism of no clinical significance. Watanabe et al. (1997) came to similar conclusions. In 3 unrelated Japanese patients with Shprintzen-Goldberg syndrome, they found that 1 was heterozygous for P1148A, 1 was homozygous for this substitution, and the third was homozygous for the wildtype allele. Among 3 healthy relatives of the SGS patient who was homozygous for P1148A, 2 (the mother and maternal grandmother) were found to be homozygous and 1 (the brother) to be heterozygous. In 161 native Japanese persons without SGS or Marfan syndrome, they found that 11 were P1148A homozygotes and 49 were heterozygotes. The estimated allele frequency of P1148A was calculated to be 0.22 among native Japanese. Wang et al. (1997) identified 5 individuals with P1148A in a mixed patient population, but none in 120 Caucasian or 50 African American controls. They found that 3 of the 5 individuals were Japanese. They also found that 8 of 25 native Chinese individuals were heterozygous and none homozygous for P1148A. Thus, Watanabe et al. (1997) concluded that P1148A is a polymorphic variant with increased frequency in Asian populations.


.0063 MARFAN SYNDROME

ECTOPIA LENTIS 1, ISOLATED, AUTOSOMAL DOMINANT, INCLUDED
FBN1, ARG974CYS
  
RCV000032871...

In a 55-year-old patient with Marfan syndrome (MFS; 154700), who had major skeletal, ocular, and cardiovascular manifestations as well as minor skin involvement, Comeglio et al. (2007) identified heterozygosity for a c.2920C-T transition in the FBN1 gene, resulting in an arg974-to-cys (R974C) substitution.

In 9 affected members of a 5-generation Chinese family with isolated ectopia lentis (ECTOL1; 129600), Yang et al. (2012) identified heterozygosity for the 2920C-T transition in exon 25 of the FBN1 gene, resulting in an R974C substitution at a highly conserved residue in the 8-cys repeat latent transforming growth factor-beta binding protein (LTBP) motif. The mutation was not found in 2 unaffected family members or in 50 ethnically matched controls.


.0064 MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME

FBN1, 2-BP DEL, 8155AA
  
RCV000033241

In a 27-year-old German woman with marfanoid-progeroid-lipodystrophy syndrome (MFLS; 616914), Graul-Neumann et al. (2010) identified heterozygosity for a de novo 2-bp deletion (8155_8156delAA) in exon 64 of the FBN1 gene, causing a frameshift that generates a premature stop codon 17 residues downstream (Lys2719AspfsTer18). The mutation was not present in either parent or in 150 unrelated controls. The patient fulfilled the clinical Ghent criteria for Marfan syndrome with 3 major features, including ectopia lentis, aortic dilatation, and dural ectasia, but also showed an extreme reduction in the amount of subcutaneous fat tissue since birth and had prominent facial lipodystrophy.


.0065 MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME

FBN1, 20-BP DEL, NT8156
  
RCV000033242

In a 20-year-old man of Irish ancestry with marfanoid-progeroid-lipodystrophy syndrome (MFLS; 616914), Goldblatt et al. (2011) identified heterozygosity for a de novo 20-bp deletion (8156_8175del) in exon 64 of the FBN1 gene, causing a frameshift resulting in a premature stop codon (Lys2719Thrfster12). The mutation was not found in his unaffected parents. The patient had marfanoid features, including arachnodactyly with generalized mild digital hyperextensibility and bilateral lens subluxations, as well as decreased subcutaneous fat of neonatal onset with a progeroid facial appearance.


.0066 MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME

FBN1, IVS64DS, G-T, +1
  
RCV000033243...

In a 3.5-year-old girl with marfanoid-progeroid-lipodystrophy syndrome (MFLS; 616914), Horn and Robinson (2011) identified heterozygosity for a de novo splice site transversion (8226+1G-T) in intron 64 of the FBN1 gene, predicted to cause use of a noncanonical splice site resulting in a frameshift of the sequence encoded by exon 65. The mutation was not found in her parents or in 150 controls. The girl had tall stature, arachnodactyly, decreased subcutaneous fat, and a progeroid facial appearance.

In a female patient with congenital partial lipodystrophy and a progeroid appearance, Romere et al. (2016) identified heterozygosity for the c.8226+1G-T mutation in the FBN1 gene, which occurred de novo. The authors noted that she also carried a heterozygous c.8222T-C missense variant in FBN1, which was predicted to be benign. No additional clinical information was provided for this patient. The patient's overnight-fasted plasma insulin level was 2-fold lower than that of controls, while maintaining euglycemia. In addition, measurement of the C-terminal cleavage product, which the authors designated 'asprosin,' showed greater reduction than would be expected from the heterozygous genotype, suggestive of a dominant-negative effect. Overexpression of the truncated mutant version of profibrillin in wildtype human dermal fibroblasts confirmed interference with the ability of those cells to secrete asprosin.


.0067 MARFAN SYNDROME

FBN1, 7-BP DEL, NT4253
  
RCV000034311

In a 16-year-old Hispanic boy with Marfan syndrome (MFS; 154700) who had moderate aortic root dilation, descending aortic dissection, mild pectus excavatum, striae atrophica, and myopia, Brautbar et al. (2010) identified heterozygosity for a 7-bp deletion (4253_4259delGCCAGTG) in exon 34 of the FBN1 gene, causing a frameshift predicted to result in a premature stop codon 55 codons downstream. The aortic dissection originated immediately distal to the origin of the left subclavian artery, extended into the abdominal aorta, and terminated at the level of the right common iliac artery. His father had died suddenly at 41 years of age from a brain aneurysm after a long history of diabetes and hypertension. Although the patient had no documentation of hypertension before his admission, the postoperative period was complicated by persistent hypertension with maximum systolic pressures of 145 mm Hg.


.0068 MARFAN SYNDROME, AUTOSOMAL RECESSIVE

FBN1, ARG2576CYS (rs147195031)
  
RCV000029780...

In a Mexican American woman with Marfan syndrome (MFS; 154700), born of a consanguineous union, Hogue et al. (2013) identified homozygosity for a C-to-T transition at nucleotide 7726 of the FBN1 gene, resulting in an arg-to-cys substitution at codon 2576 (R2576C). The severe phenotype included pectus carinatum, scoliosis, arachnodactyly, ectopia lentis, mitral valve prolapse, aortic dilation, dural ectasias, and anterior sacral meningocele. She had a narrow, asymmetric face, dolichocephaly, hypertelorism with an interpupillary distance of 6.4 cm, downslanting palpebral fissures, and kyphoscoliosis. She also had moderate hydrocephalus and mild cognitive impairment. At 18 years, her height was 155 cm (10th percentile), with a span-to-height ratio of 1.05. At 20 years of age she became pregnant. Her aortic root was 4.3 cm at 14 weeks' gestation. At 30 weeks she developed chest pain and dyspnea; CT scan showed new aortic insufficiency and dilation. Cesarean section and aortic root repair of a type A dissection were performed. Her son was small for gestational age but healthy. He had dolichocephaly, downslanting palpebral fissures, midface hypoplasia, high narrow palate, and mild right knee contracture. Ophthalmology exam and echocardiogram were normal. The proband's mother had no stigmata of Marfan syndrome; the proband's father had had a cardiac event attributed to drug abuse. He reportedly had no other features of Marfan syndrome, but was unavailable for examination. The R2576C mutation was not present in the Exome Variant Server or the database of FBN1 mutations, but was recorded as rs147195031 with an estimated heterozygosity score of 0 +/- 0.015. Hogue et al. (2013) concluded that presumably this is a hypomorphic allele of FBN1, not causing disease when present in heterozygosity but leading to severe disease in homozygosity.


.0069 MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME

FBN1, 8-BP DEL, NT8175
  
RCV000210932

In a 10-year-old Japanese girl with marfanoid-progeroid-lipodystrophy syndrome (MFLS; 616914), Takenouchi et al. (2013) identified heterozygosity for an 8-bp deletion (c.8175_8182del8) in exon 64 of the FBN1 gene, causing a frameshift predicted to result in premature termination (Arg2726GlufsTer9).


.0070 MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME

FBN1, IVS64DS, G-A, +1
  
RCV000210934...

In a 16-year-old girl with marfanoid-progeroid-lipodystrophy syndrome (MFLS; 616914), originally reported by Verloes et al. (1998), Jacquinet et al. (2014) identified heterozygosity for a de novo donor splice site mutation in intron 64 (c.8226+1G-A). Analysis of the PCR product from patient skin fibroblast culture showed that exon 64 was skipped, causing a frameshift at the beginning of exon 65 and resulting in a premature termination codon (His2685IlefsTer9).


See Also:

REFERENCES

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  143. Tynan, K., Comeau, K., Pearson, M., Wilgenbus, P., Levitt, D., Gasner, C., Berg, M. A., Miller, D. C., Francke, U. Mutation screening of complete fibrillin-1 coding sequence: report of five new mutations, including two in 8-cysteine domains. Hum. Molec. Genet. 2: 1813-1821, 1993. [PubMed: 8281141, related citations] [Full Text]

  144. Van Dijk, F. S., Hamel, B. C., Hilhorst-Hofstee, Y., Mulder, B. J. M., Timmermans, J., Pals, G., Cobben, J. M. Compound-heterozygous Marfan syndrome. Europ. J. Med. Genet. 52: 1-5, 2009. [PubMed: 19059503, related citations] [Full Text]

  145. Velinov, M., Sarfarazi, M., Young, K., Hodes, M. E., Conneally, P. M., Jackson, C. E., Tsipouras, P. Limb-girdle muscular dystrophy is closely linked to the fibrillin locus on chromosome 15. Connect. Tissue Res. 29: 13-21, 1993. [PubMed: 8339542, related citations] [Full Text]

  146. Verloes, A., Pierard, G., Lombet, J., De Paepe, A. Congenital progeroid-marfanoid syndrome: variant of Wiedemann-Rautenstrauch or new syndrome? (Abstract) Proc. Greenwood Genet. Center 17: 103-104, 1998.

  147. Wang, M., Mathews, K. R., Imaizumi, K., Beiraghi, S., Blumberg, B., Scheuner, M., Graham, J. M., Jr., Godfrey, M. P1148A in fibrillin-1 is not a mutation anymore. (Letter) Nature Genet. 15: 12 only, 1997. [PubMed: 8988160, related citations] [Full Text]

  148. Wang, M., Price, C. E., Han, J., Cisler, J., Imaizumi, K., Van Thienen, M. N., DePaepe, A., Godfrey, M. Recurrent mis-splicing of fibrillin exon 32 in two patients with neonatal Marfan syndrome. Hum. Molec. Genet. 4: 607-613, 1995. [PubMed: 7633409, related citations] [Full Text]

  149. Wang, M., Wang, J.-Y., Cisler, J., Imaizumi, K., Burton, B. K., Jones, M. C., Lamberti, J. J., Godfrey, M. Three novel fibrillin mutations in exons 25 and 27: classic versus neonatal Marfan syndrome. Hum. Mutat. 9: 359-362, 1997. [PubMed: 9101298, related citations] [Full Text]

  150. Watanabe, Y., Yano, S., Koga, Y., Yukizane, S., Nishiyori, A., Yoshino, M., Kato, H., Ogata, T., Adachi, M. P1148A in fibrillin-1 is not a mutation leading to Shprintzen-Goldberg syndrome. (Letter) Hum. Mutat. 10: 326-327, 1997. [PubMed: 9338588, related citations] [Full Text]

  151. Whiteman, P., Handford, P. A. Defective secretion of recombinant fragments of fibrillin-1: implications of protein misfolding for the pathogenesis of Marfan syndrome and related disorders. Hum. Molec. Genet. 12: 727-737, 2003. [PubMed: 12651868, related citations] [Full Text]

  152. Whiteman, P., Smallridge, R. S., Knott, V., Cordle, J. J., Downing, A. K., Handford, P. A. A G1127S change in calcium-binding epidermal growth factor-like domain 13 of human fibrillin-1 causes short range conformational effects. J. Biol. Chem. 276: 17156-17162, 2001. [PubMed: 11278305, related citations] [Full Text]

  153. Whiteman, P., Willis, A. C., Warner, A., Brown, J., Redfield, C., Handford, P. A. Cellular and molecular studies of Marfan syndrome mutations identify co-operative protein folding in the cdEGF12-13 region of fibrillin-1. Hum. Molec. Genet. 16: 907-918, 2007. [PubMed: 17324963, related citations] [Full Text]

  154. Yang, G., Chu, M., Zhai, X., Zhao, J. A novel FBN1 mutation in a Chinese family with isolated ectopia lentis. Molec. Vis. 18: 945-950, 2012. [PubMed: 22539873, images, related citations]

  155. Zhang, H., Hu, W., Ramirez, F. Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils. J. Cell Biol. 129: 1165-1176, 1995. [PubMed: 7744963, related citations] [Full Text]


Marla J. F. O'Neill - updated : 11/12/2020
Ada Hamosh - updated : 02/27/2019
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Marla J. F. O'Neill - updated : 4/28/2016
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Creation Date:
Victor A. McKusick : 5/7/1991
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carol : 11/20/2013
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carol : 9/30/2013
carol : 4/11/2013
carol : 3/26/2013
terry : 3/22/2013
carol : 3/12/2013
terry : 3/12/2013
carol : 1/25/2013
alopez : 11/13/2012
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carol : 10/4/2012
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terry : 6/14/2011
carol : 4/7/2011
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terry : 8/5/2010
terry : 8/5/2010
carol : 7/12/2010
carol : 7/1/2010
carol : 5/17/2010
carol : 4/2/2010
mgross : 3/18/2010
terry : 3/18/2010
wwang : 1/28/2010
terry : 1/27/2010
joanna : 11/9/2009
carol : 11/5/2009
terry : 10/30/2009
wwang : 6/25/2009
terry : 6/3/2009
wwang : 5/21/2009
ckniffin : 5/14/2009
wwang : 5/4/2009
ckniffin : 4/27/2009
ckniffin : 4/16/2009
ckniffin : 4/16/2009
wwang : 3/30/2009
terry : 3/26/2009
mgross : 2/17/2009
wwang : 11/12/2008
wwang : 6/30/2008
ckniffin : 6/16/2008
wwang : 3/26/2008
terry : 3/18/2008
alopez : 3/10/2008
carol : 10/2/2007
terry : 10/1/2007
alopez : 8/27/2007
terry : 8/16/2007
wwang : 6/11/2007
ckniffin : 5/17/2007
wwang : 4/2/2007
ckniffin : 9/21/2006
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terry : 4/24/2000
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terry : 6/23/1997
terry : 6/20/1997
joanna : 5/8/1997
alopez : 4/28/1997
alopez : 4/28/1997
alopez : 4/28/1997
alopez : 4/24/1997
alopez : 4/24/1997
terry : 4/23/1997
terry : 3/21/1997
terry : 3/17/1997
terry : 1/30/1997
terry : 1/30/1997
terry : 1/29/1997
terry : 1/27/1997
mark : 1/27/1997
mark : 1/21/1997
mark : 10/23/1996
carol : 9/26/1996
carol : 7/22/1996
carol : 7/22/1996
terry : 7/15/1996
terry : 7/12/1996
terry : 7/11/1996
mark : 6/19/1996
mark : 6/19/1996
mark : 6/19/1996
mark : 6/19/1996
mark : 6/7/1996
mark : 3/30/1996
mark : 3/21/1996
joanna : 3/20/1996
terry : 3/12/1996
mark : 3/12/1996
terry : 3/5/1996
mark : 2/1/1996
terry : 1/30/1996
mark : 12/13/1995
mark : 11/14/1995
terry : 10/25/1995
mimadm : 11/6/1994
jason : 7/19/1994
davew : 6/27/1994

* 134797

FIBRILLIN 1; FBN1


Alternative titles; symbols

FIBRILLIN; FBN


HGNC Approved Gene Symbol: FBN1

SNOMEDCT: 19346006, 254090007, 763839005, 765187004;   ICD10CM: Q87.4, Q87.40;   ICD9CM: 759.82;  


Cytogenetic location: 15q21.1     Genomic coordinates (GRCh38): 15:48,408,313-48,645,709 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
15q21.1 Acromicric dysplasia 102370 Autosomal dominant 3
Ectopia lentis, familial 129600 Autosomal dominant 3
Geleophysic dysplasia 2 614185 Autosomal dominant 3
Marfan lipodystrophy syndrome 616914 Autosomal dominant 3
Marfan syndrome 154700 Autosomal dominant 3
MASS syndrome 604308 Autosomal dominant 3
Stiff skin syndrome 184900 Autosomal dominant 3
Weill-Marchesani syndrome 2, dominant 608328 Autosomal dominant 3

TEXT

Description

Fibrillin is the major constitutive element of extracellular microfibrils and has widespread distribution in both elastic and nonelastic connective tissue throughout the body. The cDNA was identified in 1991 and was mapped coincident with the locus for Marfan syndrome. Subsequent studies confirmed that mutations in the FBN1 gene are the major cause of Marfan syndrome (MFS; 154700).


Cloning and Expression

The connective tissue protein fibrillin was isolated from the medium of human fibroblast cell cultures and was characterized and named by Sakai et al. (1986). Using monoclonal antibodies specific for fibrillin, they demonstrated its widespread distribution in the connective tissue matrices of skin, lung, kidney, vasculature, cartilage, tendon, muscle, cornea, and ciliary zonule. The molecular weight of fibrillin is about 350,000 Da. Sakai et al. (1991) pointed out that fibrillin contains approximately 14% cysteine, of which one-third appears to be in the free reactive sulfhydryl form.

Maslen et al. (1991) isolated cDNA clones for the fibrillin gene. Corson et al. (1993) and Pereira et al. (1993) completed characterization of the fibrillin cDNA, elucidated the exon/intron organization of the gene, and derived a physical map of the locus. The profibrillin sequence encodes a 2,871-amino acid protein which, excluding the signal peptide, is arranged into 5 structurally distinct regions. The largest of these regions, comprising about 75% of the protein, are the 46 EGF-like repeats, cysteine-rich domains originally found in human epidermal growth factor (131530). Forty-three of these repeats satisfy the consensus for calcium binding, an event that may mediate protein-protein interactions, and are called calcium-binding EGF-like repeats (cbEGFs). A mutation in one of these EGF-like repeats was identified in a Marfan syndrome patient; see 134797.0001. The tandem repetition of EGF-like domains is interrupted by 8 cysteine motifs that have homology to a domain first recognized in transforming growth factor beta-1-binding protein (TGFBR1; 190181), called a TB domain. Almost all of the EGF-like repeats are encoded by single exons. The other 4 regions include a unique amino-terminal stretch of basic residues, an adjacent second cysteine-rich region, a proline-rich domain, and the carboxy terminus.

Using immunohistochemical analysis, Quondamatteo et al. (2002) investigated the distribution of fibrillin 1 and fibrillin 2 (FBN2; 612570) in human embryonic and early fetal tissues between gestational weeks 5 and 12. Both fibrillins were widely distributed. In most embryonic and early fetal organs, such as skin, lung, heart, aorta, central nervous system anlage, nerves, and ganglia, both fibrillins followed the same temporospatial pattern of distribution. However, in kidney, liver, rib anlagen, and notochord, distribution of FIB1 and FIB2 differed.


Gene Structure

The fibrillin gene is relatively large, and the coding sequence is divided into 65 exons (Corson et al., 1993; Pereira et al., 1993). Corson et al. (1993) described 3 alternatively spliced exons at the 5-prime end, which they termed exon B, exon A, and exon C. A CpG island was identified that spans the first 2 alternatively spliced exons.

Biery et al. (1999) estimated the size of the FBN1 gene to be 200 kb.


Mapping

Upon identification of intragenic polymorphisms within the FBN1 gene, Dietz et al. (1991) and Lee et al. (1991) demonstrated linkage between the FBN1 locus and the previously mapped Marfan syndrome locus at 15q15-q21.1. Using clones derived from fibrillin cDNA as probes in isotopic and nonisotopic in situ hybridization studies, Magenis et al. (1991) mapped the human fibrillin gene to 15q21.1.

Velinov et al. (1993) demonstrated linkage between the FBN1 locus and the locus for limb-girdle muscular dystrophy (LGMD2A; 253600), which had previously been mapped to 15q15.1-q21.1. In a large Amish kindred segregating LGMD, they found a maximum lod score of 9.135 at theta = 0.04.

By analysis of a mapping panel of mouse/hamster somatic hybrid cell lines, Li et al. (1993) demonstrated that the murine homolog of the FBN1 gene is located on chromosome 2.


Gene Function

Corson et al. (1993) demonstrated that fibrillin molecules bind calcium.

Using in situ hybridization and immunohistochemical analysis, Zhang et al. (1995) showed that Fib1 and Fib2 were differentially expressed in a temporal and spatial manner during mouse and rat development. In the majority of cases, Fib2 transcripts appeared earlier and accumulated for a shorter period of time than Fib1 transcripts. Synthesis of Fib1 correlated with late morphogenesis and the appearance of well-defined organ structures. Conversely, Fib2 synthesis coincided with early morphogenesis and the beginning of elastogenesis. Zhang et al. (1995) proposed that FIB1 provides mostly force-bearing structural support, whereas FIB2 predominantly regulates the early process of elastic fiber assembly.

Trask et al. (1999) found that human FIB1 and FIB2 homodimerized via an N-terminal region and that the interaction was stabilized by disulfide bonds. Dimer formation occurred intracellularly, suggesting that the process of fibrillin aggregation initiates early after biosynthesis of the molecules. No heterodimers of FIB1 and FIB2 were observed, suggesting that the pro- and gly-rich domains of FIB1 and FIB2, respectively, determine the specificity of dimer formation.

Lin et al. (2002) showed that the N terminus of human FIB1 could assemble in a linear fashion with the C terminus of another FIB1 molecule to form homotypic FIB1 microfibrils in the presence of calcium. FIB1 could interact similarly with FIB2 to form heterotypic microfibrils, but FIB2 N- and C-terminal constructs showed no significant interaction with one another. In dermal fibroblasts from a 1-year-old donor, both FIB1 and FIB2 were detected in a microfibrillar network. In contrast, osteoblasts from a 42-year-old donor showed a microfibrillar network made up of FIB1 alone. Lin et al. (2002) concluded that FIB1 can form microfibrillar structures in the absence of FIB2, and that FIB2 can occur in microfibrils with FIB1.

Using immunohistochemical analysis and immunogold microscopy of embryonic and adult mouse, Tsutsui et al. (2010) found that Adamtsl6 (THSD4; 614476) colocalized with fibrillin-1 in fibrillar structures of various elastic tissues. The recombinant Adamtsl6-beta isoform interacted with the N-terminal half of fibrillin-1 in a dose-dependent manner. When transfected into human osteosarcoma cells, both Adamtsl6 isoforms promoted formation of fibrillin-1 microfibrils in a dose-dependent manner that was independent of fibrillin-1 synthesis. Fibrillin-1 deposition in the extracellular matrix was enhanced in transgenic mice overexpressing Adamtsl6-beta in cartilaginous tissues. Tsutsui et al. (2010) concluded that ADAMTSL6 promotes the assembly of fibrillin-1 microfibrils.

Duerrschmid et al. (2017) noted that Romere et al. (2016) had shown that obesity in humans and mice is associated with a pathologic increase in the C-terminal cleavage product of profibrillin, asprosin. To ascertain whether asprosin stimulates appetite, Duerrschmid et al. (2017) administered recombinant asprosin subcutaneously to wildtype mice, and observed greater food intake over the next 24 hours. Daily subcutaneous injections of asprosin resulted in hyperphagia and a significant increase in adiposity. Adenovirus-mediated overexpression of human FBN1 resulted in an approximately 2-fold increase in plasma asprosin and a similar hyperphagic response; the increase in adiposity was potentiated when the mice were given a high-fat diet. The authors observed that exposure to recombinant asprosin acutely induced activation of known orexigenic AgRP+ neurons within the hypothalamus by increasing the firing frequency as well as the resting membrane potential. Ablation of AgRP+ neurons completely eliminated asprosin's orexigenic drive in mice on normal chow. However, when exposed to a high-fat diet, the ablated mice responded to asprosin, suggesting that a highly palatable diet is able to engage neuronal populations differently from those involved in normal hunger signals. Experiments with hypothalamic cells exposed to various inhibitors revealed that asprosin directly activates orexigenic AgRP+ neurons via a cAMP-dependent pathway. Duerrschmid et al. (2017) showed that this signaling causes inhibition of downstream anorexigenic proopiomelanocortin (POMC; 176830)-positive neurons in a GABA-dependent manner, which results in appetite stimulation and a drive to accumulate adiposity and body weight.


Molecular Genetics

Marfan Syndrome

Data from several studies suggested fibrillin as a possible candidate gene for Marfan syndrome (154700). Fibrillin was immunolocalized to the ciliary zonule (Sakai et al., 1986), a ligamentous structure consisting mainly of fibrillin microfibrils which is characteristically affected in the Marfan syndrome. Hollister et al. (1990) demonstrated abnormal immunohistochemical patterns in the skin and cultured fibroblasts of patients with the Marfan syndrome. By pulse-chase analysis, Milewicz et al. (1992) demonstrated reproducible patterns of abnormal fibrillin-1 synthesis, secretion, or extracellular matrix utilization in the vast majority of fibroblast cell cultures from Marfan syndrome patients. Furthermore, the Marfan phenotype had been mapped by linkage studies to the same region of chromosome 15 that contained the fibrillin gene. The demonstration of linkage between the fibrillin gene (as recognized by a TaqI restriction site polymorphism) and the Marfan phenotype, combined with the demonstration of point mutations within the fibrillin gene in patients with classic Marfan syndrome (Dietz et al., 1991), concluded the proof that FBN1 is 'the Marfan gene.' In a letter received February 4, 1992, Hayward et al. (1992) stated that of the 2 fibrillin mutations discovered up to that time, arg239-to-pro (now designated as codon 1137; 134797.0001) had been found twice in 111 cases and cys1409-to-ser (now designated as codon 2307; 134797.0002) had been found once in 140 cases (mutations being scored once for each sporadic case and once for each family segregating the gene). They concluded that there are likely to be many different FBN1 mutations responsible for the Marfan syndrome.

Dietz et al. (1992) pointed out that all 5 missense mutations characterized to that time occurred within the EGF-like repeats of the FBN1 gene. In addition, 4 of the 5 involved the substitution of cysteine residues, and 3 of the 5 substituted the third cysteine in the EGF-like motif consensus sequence.

By screening 44 probands with Marfan syndrome or related phenotypes for alterations in the entire fibrillin coding sequence of 9.3 kb by single-strand conformation analysis, Tynan et al. (1993) found 4 unique mutations in unrelated patients. One was a 17-bp deletion and 3 were missense mutations, 2 of which involved 8-cysteine motifs. Another missense mutation was found in 2 unrelated patients with annuloaortic ectasia but was present in unaffected relatives and controls from various ethnic backgrounds. Their results suggested that most Marfan syndrome families carry unique mutations; the original arg1137-to-pro mutation, found twice in a pool of 43 patients by Dietz et al. (1991), remained the only example of a mutation described in more than 1 family.

Dietz et al. (1993) described 4 novel FBN1 mutations by screening the FBN1 gene, including the 5-prime coding sequence. Two of them were missense mutations that, like all of the previously identified ones, were associated with classic and moderate to severe disease and occurred at residues with putative significance for calcium binding to EGF-like domains. In contrast, the 2 novel mutations that created premature signals for termination of translation of mRNA were associated with reduction in the amount of mutant allele transcript and produced a range of phenotypic severity. The patient with the lowest amount of mutant transcript had an extremely mild phenotype that did not satisfy the diagnostic criteria for Marfan syndrome. The data were interpreted as supporting a role for altered calcium binding to EGF-like domains in the pathogenesis of Marfan syndrome and suggested a dominant-negative mechanism for the pathogenesis of this disorder.

Using pulse-chase studies with (35)S-cysteine-labeled fibrillin on fibroblast strains from 55 patients with Marfan syndrome, Aoyama et al. (1994) found that the quantitation of the soluble intracellular and insoluble extracellular fibrillin allowed discrimination of 5 groups. Groups I and II synthesized reduced amounts of normal-sized fibrillin, while synthesis was normal in groups III, IV, and V. When extracellular fibrillin deposition was measured, groups I and III deposited between 35 and 70% of control values, groups II and IV less than 35%, and group V more than 70%. A deletion mutant with a low transcript level from the mutant allele and 7 additional patients had the group I protein phenotype. Disease in these patients is proposed to be caused by a reduction in microfibrils associated with either a null allele, an unstable transcript, or an altered fibrillin product synthesized in low amounts. In 68% of the Marfan syndrome individuals (groups II and IV), a dominant-negative effect was invoked as the main pathogenetic mechanism. Aoyama et al. (1994) proposed that products made by the mutant allele in these fibroblasts interfered with microfibril formation. Seven of the 9 known missense mutations, giving rise to abnormal but normal-sized fibrillin molecules, were in group IV. In 4 of the 55 fibroblast strains, no defect in fibrillin metabolism could be identified with the pulse-chase method. All 4 were sporadic cases and, therefore, linkage studies with polymorphic markers could not be checked to determine relationship to the FBN1 locus. One of the possibilities considered by Aoyama et al. (1994) was the involvement of some other protein that is associated with microfibrils, such as elastin (130160), thrombospondin (188062), microfibril-associated glycoprotein (156790), emilin (130660), or fibrillin-2 (121050).

Eldadah et al. (1995) addressed the question of whether Marfan syndrome results from a deficiency of wildtype fibrillin (haploinsufficiency), from a dominant-negative effect in which mutant fibrillin monomers disrupt the function of the wildtype protein encoded by the normal allele, or from a dynamic and variable interplay between these 2 pathogenetic mechanisms. To address this issue in a cell culture system, they stably transfected normal human and murine fibroblasts with a mutant fibrillin allele from a patient with severe Marfan syndrome. The mutation was a G-to-A transition at position +1 of the donor splice site of intron 2 that resulted in the skipping of exon 2, a frameshift, and a subsequent premature termination codon in exon 4. Immunohistochemical analysis of the resultant cell lines demonstrated markedly diminished fibrillin deposition and disorganized microfibrillar architecture. Pulse-chase studies showed normal levels of fibrillin synthesis but substantially reduced deposition into the extracellular matrix. These data illustrated that expression of a mutant fibrillin allele, on a background of 2 normal alleles, is sufficient to disrupt normal microfibrillar assembly and to reproduce the Marfan cellular phenotype. The findings in cell culture underscored the importance of the fibrillin amino-terminus in normal microfibrillar assembly and suggested that expression of the human extreme 5-prime fibrillin coding sequence may be sufficient, in isolation, to produce an animal model of the Marfan syndrome. Lastly, this substantiation of a dominant-negative effect offered mutant allele knockout as a potential strategy for gene therapy (see Dietz and Pyeritz, 1994).

In a 66-year-old female with Marfan syndrome, Hewett et al. (1994) found a heterozygous G-to-A mutation at nucleotide 3952 of the FBN1 gene, resulting in a C1223Y substitution within an EGF-like domain (134797.0022). Dietz et al. (1995) found the C1223Y mutation in the FBN1 gene in a patient with Marfan syndrome who also had features of Shprintzen-Goldberg syndrome (SGS; 182212), including craniosynostosis and mental retardation. Kosaki et al. (2006) also reported a patient who had features of both disorders and a mutation in the FBN1 gene (C1221Y; 134797.0045). It may be significant that both of these mutations reside in the same EGF-like domain of fibrillin (Doyle et al., 2012).

Among the many clinical applications of PCR is its potential use in preimplantation diagnosis of genetic disorders. Eldadah et al. (1995) discussed the use of PCR in the molecular detection of heterozygous genetic mutations. In principle, performing PCR on single blastomeres from early cleavage stage (6- to 8-cell) human embryos should enable reliable determination of disease status for certain inherited conditions. However, reports of misdiagnoses using this technique diminished enthusiasm for its widespread clinical use. A principal source of error is the propensity for genome-targeted PCR to amplify one allele exclusively in reactions assaying a single heterozygous diploid cell. Complete reaction failure is also common. Employing the Marfan syndrome as a paradigm, Eldadah et al. (1995) developed a reliable, RT-PCR-based method for genotyping single cells that overcomes these obstacles. The technique should facilitate accurate preimplantation diagnosis of Marfan syndrome and other selected genetic diseases caused by heterozygous or compound heterozygous mutations.

The large size of the FBN1 gene as well as other factors precluded routine mutation screening for presymptomatic and prenatal diagnosis. Judge et al. (2001) identified and localized highly polymorphic microsatellite markers that fall within 1 Mb of FBN1. Complete haplotype heterozygosity was observed in a population of 50 unrelated control individuals when the flanking markers and existing intragenic polymorphisms were used in combination. They demonstrated the usefulness of haplotype segregation analysis in the presymptomatic diagnosis and counseling of families showing atypical or equivocal manifestations of MFS.

Downing et al. (1996) described the nuclear magnetic resonance-derived structure of a covalently linked pair of calcium-binding epidermal growth factor-like domains from human fibrillin-1. The 2 domains are in a rigid, rod-like arrangement, stabilized by interdomain calcium-binding and hydrophobic interactions. They proposed a model for the arrangement of fibrillin monomers in microfibrils that reconciles structural and antibody binding data, and described a set of disease-causing mutations that provide the first clues to the specificity of the interactions of the calcium-binding EGF domains. The residues involved in stabilizing the domain linkage are highly conserved in fibrillin, fibulin (135820), thrombomodulin (188040), and the low density lipoprotein receptor (606945). They suggested that all reported mutations can be divided into 3 groups according to their effects on disulfide bond formation, calcium binding, and intra- and intermolecular interactions.

Liu et al. (1996) developed a simple and highly efficient long RT-PCR approach for rapid detection of exon-skipping mutations in FBN1. This approach led to the identification of 6 different exon skipping mutations, including 5 not previously reported and 1 recurring mutation. Liu et al. (1996) extracted total RNA from cultured fibroblasts from Marfan probands and the entire FBN1 cDNA was amplified in 3 overlapping fragments 3-4 kb in size. They compared the restriction patterns of long RT-PCR products amplified from normal and patient samples and identified 1 mutation in a 4 kb fragment which included exons 1-31, 2 mutations in fragments from exons 28-52, and 3 mutations in fragments spanning exons 47-65. DNA from the altered bands was gel purified, reamplified, and directly sequenced. In a panel of 60 Marfan probands Liu et al. (1996) identified 6 exon-skipping mutations. All skipped exons encoded calcium-binding epidermal growth factor (EGF)-like domains and maintained the reading frame. In 5 probands, exon skipping was due to point mutations in splice site sequences and in 1 case it was due to a 6-bp deletion in a donor splice site. Fibrillin synthesis and secretion was normal. Deposition of newly synthesized fibrillin into extracellular matrix was very much reduced. They carried out genotype/phenotype correlations and concluded that patients with in-frame skipping of an exon in their FBN transcripts tended to have a severe phenotype. Liu et al. (1996) demonstrated that the mutant mRNA missing an in-frame exon is stable and is only slightly shorter than normal fibrillin. They also demonstrated that both the normal and the abnormal forms are secreted and both forms of fibrillin molecules participate in the formation of microfibrils. Liu et al. (1996) concluded that the abnormal fibrillin forms therefore have a dominant-negative effect.

Although many of the mutation reports published prior to 1993 used a codon numbering system based upon a partial cDNA sequence, this entry uses the numbering system of Pereira et al. (1993) which reflects the characterization of the entire coding sequence for fibrillin.

Collod et al. (1996) described a software package and computerized database to facilitate search for mutations in the FBN1 gene. By the fall of 1995, 63 mutations in the FBN1 gene had been reported. These were almost entirely private, for the most part missense, nonrecurrent, and widely distributed throughout the gene. The mutations were presented in tabular form. The database was made available in Macintosh format on floppy disc. Collod-Beroud et al. (1997) described the second version of the computerized Marfan database, which contained 89 entries. The FBN1 gene has been found to harbor mutations related to a spectrum of conditions phenotypically related to MFS. These mutations are private, essentially missense, generally nonrecurrent, and widely distributed throughout the gene. To that time, no clear genotype/phenotype relationship had been observed except for the localization of neonatal mutations in a cluster between exons 24 and 32.

In 2 male patients with dilation of the aortic root, 1 of whom underwent acute dissection of the ascending thoracic aorta, Milewicz et al. (1996) identified 2 distinct heterozygous missense mutations in the FBN1 gene that were not found in 80 controls or 37 patients with thoracic aortic aneurysm. Both patients had high-arched palates and mitral valve prolapse, and both had undergone inguinal herniorrhaphies in their early 30s. One man had mild pectus excavatum and pes cavus with mild contractures of the toes, and the other had mild thoracic scoliosis.

Hayward et al. (1997) screened all 65 exons of the FBN1 gene in 20 Marfan syndrome families where at least 2 affected individuals were characterized and available for analysis, another 30 families with only 1 affected member available for analysis, and in 10 sporadic cases. In large well-characterized families with more than 4 affected individuals, the detection rate for mutations rose to 78% (7 of 9). In families where only 1 affected member was available, the mutation detection rate was 17% (5 of 30), and in sporadic cases it was 20% (2 of 10). In addition, they found 8 neutral polymorphisms. Twelve of the 17 disease-causing mutations had not been previously described, thus raising the total number of different FBN1 mutations reported to 85 in 94 unrelated cases. Both SSCP and heteroduplex analysis were used in the analyses of all 60 probands.

Hayward and Brock (1997) reviewed 97 different disease-associated single mutations in the FBN1 gene. Most of these mutations have been nonrecurring and, with the exception of the severe neonatal form of Marfan syndrome, spread throughout the gene with no obvious phenotypic association. Hayward and Brock (1997) stated that many cases of Marfan syndrome remain whose cause of abnormality is still undefined.

Montgomery et al. (1998) described molecular mechanisms underlying subdiagnostic variants of Marfan syndrome. In 1 family, an R1265C mutation (134797.0031) was found in mother and son with fully typical Marfan syndrome. Two other sons of the woman were said to be affected but haplotype and mutation analyses indicated that they could not have carried the mutation, despite the suggestive clinical findings. In a second family, multiple members were thought to have a nonspecific connective tissue disorder with dolichostenomelia, joint hypermobility, kyphoscoliosis, pes planus, positive wrist and thumb signs, striae distensae, early myopia, and myxomatous mitral leaflets with mitral valve prolapse. Because of the lack of dislocated lens or aortic dilatation, they were thought not to fulfill the diagnostic criteria for Marfan syndrome. However, an R1170H mutation was found in the FBN1 gene (134797.0032). In a third family, the proband had severe manifestations of Marfan syndrome, including aortic root dilatation to 8 cm, and was found to carry an R529X mutation in the FBN1 gene (134797.0033). The proband's mother, who was 60 years of age at the time of report, showed only joint hypermobility, pes planus, and striae distensae over the abdomen and trunk. There was no myopia or lens dislocation, and aortic measurements were within normal limits. The mother was found to be a mosaic for the R529X mutation.

The patients reported by Montgomery et al. (1998) were said to have subdiagnostic variants of the Marfan syndrome because they did not satisfy the diagnostic criteria proposed by De Paepe et al. (1996). According to these revised criteria, at least 1 of 4 manifestations with major diagnostic significance (lens dislocation, aortic dilatation or dissection, dural ectasia, or specific combinations of skeletal features) and involvement of at least one other system must be present for Marfan syndrome to be diagnosed in an individual with an unequivocally affected first-degree relative.

Chikumi et al. (2000) stated that more than 137 different FBN1 mutations had been reported. In Japanese patients, they identified 2 additional novel mutations and a recurrent de novo mutation, IVS2DS+1G-A (134797.0035).

Collod-Beroud et al. (1998) stated that over 137 FBN1 mutations had been reported and that these were spread throughout most the gene. Most of them are missense mutations, affecting either the conserved cysteine residues or residues of the calcium-binding consensus sequence of the calcium-binding EGF (cbEGF) motifs.

Fibrillin-1 consists mainly of 47 EGF domains, 43 of which are cbEGF domains, and 7 TGFBR1 (190181)-like (TB) domains interspersed among them. McGettrick et al. (2000) used proteases to probe structural changes caused by the asn2144-to-ser FBN1 calcium-binding mutation (134797.0009) in a TB6-cbEGF32 and a cbEGF32-33 domain pair, and a protein-engineered asn2183-to-ser mutation in the cbEGF32-33 pair. N-terminal sequence analysis of domain pairs digested in the presence and absence of calcium showed that domain interactions between TB6 and cbEGF32 are calcium-independent; domain interactions between cbEGF32 and cbEGF33 are calcium-dependent; and an asn-to-ser mutation causes increased proteolytic susceptibility only when located in cbEGF33, suggesting a key role for interdomain calcium-binding in rigidifying cbEGF domain linkages. The authors concluded that the structural consequences of calcium-binding mutations in fibrillin-1 cbEGF domains may be influenced by domain context.

Most extracellular proteins consist of various modules with distinct functions, e.g., the cbEGF module, mutations in which can lead to a variety of genetic disorders. Reinhardt et al. (2000) described structural and functional consequences of 2 typical mutations in cbEGF modules of fibrillin-1 that result in Marfan syndrome: N548I (134797.0010) and E1073K (134797.0038). Large wildtype and mutated polypeptides were recombinantly expressed in mammalian cells. Neither mutation altered synthesis and secretion of the polypeptides into the culture medium. Electron microscopy showed minor structural differences between wildtype and mutated forms. Mutated polypeptides were significantly more susceptible to proteolytic degradation by a variety of proteases as compared with their wildtype counterparts. Most of the sensitive cleavage sites were mapped close to the mutations, indicating local structural changes within the mutated cbEGF modules. Other cleavage sites, however, were observed at distances beyond the domain containing the mutation, suggesting longer range structural effects within tandemly repeated cbEGF modules. Reinhardt et al. (2000) suggested that proteolytic degradation of mutated fibrillin-1 may play an important role in the pathogenesis of Marfan syndrome and related disorders. They identified plasmin as a fibrillin-1 degrading enzyme and suggested that it could play a role in degradation of mutated fibrillin-1 in a pathologic situation since it has wide substrate specificity and is available in extracellular matrices at sites where fibrillin-1 and microfibrils are expressed. With smooth muscle cell proliferation, macrophage infiltration metalloproteases may be released, potentially enhancing fibrillin-1 degradation as disease progresses.

In cultured human dermal fibroblasts treated with recombinant fibrillin-1 fragments containing the RGD (arg-gly-asp) integrin-binding motif of fibrillin-1, Booms et al. (2005) observed significant upregulation of the matrix metalloproteinases MMP1 (120353) and MMP3 (185250). They suggested that fibrillin fragments might have pathogenic effects by leading to upregulation of MMPs, which might in turn be involved in the progressive breakdown of microfibrils thought to play a role in MFS.

The G1127S mutation in FBN1 (134797.0021) is located in cbEGF13, and experiments on isolated cbEGF13 and a cbEGF13-14 pair indicated that the mutation caused defective folding of cbEGF13, but not cbEGF14. Whiteman et al. (2001) examined the structural consequences of the G1127S mutation in a covalently linked cbEGF12-13 pair and a cbEGF12-14 triple-domain construct. Their findings suggested that covalent linkage of cbEGF12 preserves the native-like fold of cbEGF13 with G1127S, and that conformational effects introduced by G1127S are localized to cbEGF13. Whiteman et al. (2001) concluded that missense mutations in FBN1 cbEGF domains can cause short-range structural effects in addition to the long-range effects previously observed with the E1073K mutation in cbEGF12.

Matyas et al. (2002) evaluated denaturing HPLC for mutation detection in Marfan syndrome, concluding that this method is highly sensitive. With a flow chart they planned a strategy for FBN1 mutation screening.

Robinson et al. (2002) stated that at least 337 mainly unique mutations in the FBN1 gene had been reported in the Marfan syndrome. The clinical presentation of the fibrillinopathies caused by FBN1 mutations ranged from isolated ectopia lentis (ECTOL1; 129600) to neonatal Marfan syndrome, which generally leads to death within the first 2 years of life.

Katzke et al. (2002) used temperature-gradient gel electrophoresis (TGGE) screening of all 65 FBN1 exons to study 126 individuals with Marfan syndrome and related fibrillinopathies. They identified a total of 53 mutations, of which 33 were described for the first time. Several mutations were identified in individuals with fibrillinopathies other than classic Marfan syndrome, including aneurysm of the ascending aorta with only minor skeletal anomalies, and several individuals with only skeletal and ocular involvement. The mutation detection rate in this study was 42% overall, but was only 12% in individuals not fulfilling the diagnostic criteria of Marfan syndrome, suggesting that clinical overdiagnosis is one reason for a low detection rate observed for FBN1 mutation analysis.

Robinson and Godfrey (2000) provided an extensive review of the molecular physiology and pathophysiology of Marfan syndrome and related fibrillinopathies.

Kodera et al. (2002) sequenced the FBN1 gene in 22 Japanese patients with scleroderma and found that a CT insertion in the 5-prime untranslated region of exon A had a significant negative association with disease.

To investigate the effect of misfolding on the trafficking of fibrillin-1 from fibroblast cells, Whiteman and Handford (2003) studied 3 missense mutations (C1117Y, 134797.0025; C1129Y, 134797.0044; and G1127S, 134797.0021) in the cbEGF13 domain. Both C1117Y and C1129Y, expressed as recombinant fragments of fibrillin-1, were retained and accumulated within cells. Both underwent core glycosylation but lacked the complex glycosylation observed in the secreted wildtype fragment, suggesting retention in the endoplasmic reticulum (ER). Coimmunoprecipitation experiments showed association with the ER chaperone calreticulin (CALR; 109091), but not calnexin (CANX; 114217), 78-kD glucose-regulated protein (HSPA5; 138120), or protein disulfide isomerase (P4HB; 176790). In contrast, G1127S, which caused a moderate change in the EGF domain fold, showed a pattern of glycosylation and trafficking profile indistinguishable from the wildtype fragment. Whiteman and Handford (2003) proposed that G1127S may cause disease through an extracellular dominant-negative effect. They further suggested that the observed ER retention of C1117Y and C1129Y is caused either by an intracellular dominant-negative effect or haploinsufficiency.

Collod-Beroud et al. (2003) provided an update on their database of mutations in the FBN1 gene and described the creation of an FBN1 polymorphism database. They stated that 563 FBN1 mutations had been identified. They provided a tabulation of 56 recurrent mutations found in the FBN1 gene. These included the 3037G-A mutation (134797.0036), which had been reported 6 times, and the IVS46+5 G-A mutation (134797.0039), which had been reported 9 times.

Hutchinson et al. (2003) described an FBN1 deletion patient (46,XXdel(15)(q15q22.1)) whose fibrillin-1 protein and mRNA levels were significantly higher than expected for a single FBN1 allele. RNA analyses identified a variable reduction in total FBN1 transcript (78 to 27%) in 3 related individuals carrying a premature termination codon (PTC)-causing mutation compared with unaffected control individuals. Both pulse-chase analysis of fibrillin-1 biosynthesis and RNase protection analyses demonstrated that these differences were due to variation in the expression of the normal FBN1 allele and not nonsense-mediated decay (NMD) of mutant RNA. The authors suggested that differences in normal FBN1 expression may contribute to the clinical variability seen within families with Marfan syndrome.

Singh et al. (2006) screened the 5-prime alternatively spliced exons B, A, and C of the FBN1 gene in 41 patients with Marfan syndrome or with features of Marfan syndrome but not fulfilling strict interpretation of the Ghent criteria, and who were negative for FBN1 mutations in exons 1 to 65. The authors identified 5 sequence variants in the 5-prime upstream region of the FBN1 gene in 6 unrelated patients, 2 of whom fulfilled the Ghent criteria. Preliminary studies suggested that the variants may interfere with transcription.

Using multiplex ligation-dependent probe amplification (MLPA) and high-density SNP arrays, Matyas et al. (2007) analyzed the FBN1 gene in 101 unrelated individuals with MFS or related phenotypes in whom no mutations had been detected by standard genetic testing. In 2 patients with MFS, they identified large FBN1 deletions of 26.8 kb and 302.5 kb (134797.0048), respectively. Negative family histories suggested that both deletions arose de novo. Both deletions involved the putative regulatory and promoter regions of the FBN1 gene; true haploinsufficiency was confirmed by transcript analysis in 1 patient.

Whiteman et al. (2007) showed that an FBN1 fragment (cbEGF11-22) containing any of 4 pathogenic substitutions that inhibit calcium binding in cbEGF13 altered the folding of wildtype cbEGF12, resulting in retention of the cbEGF11-22 fragment in the ER.

Comeglio et al. (2007) analyzed the FBN1 gene in 508 consecutive patients and identified mutations in 90 (82%) of 110 patients with a diagnosis of 'classic' Marfan syndrome, 84 (27%) of 315 with an 'incomplete Marfan phenotype,' and 19 (50%) of 38 patients with isolated ectopia lentis. No mutations were detected in 45 patients with isolated ascending thoracic aortic aneurysm (see 607086).

Aragon-Martin et al. (2010) analyzed the FBN1 gene in 36 UK patients with ectopia lentis who did not fulfill the Ghent criteria for Marfan syndrome and identified causative mutations in 23 (64%), primarily in the 5-prime region of the gene. The authors noted that this represented an improved mutation detection rate over their previous study (Comeglio et al., 2007), due to rescreening of patients who were negative for mutation by SSCA with the more sensitive dHPLC detection method.

Brautbar et al. (2010) reported 3 patients with descending thoracic aortic dissections who were subsequently found to have heterozygous mutations in the FBN1 gene (see, e.g., 134797.0067). All 3 had aortic root dilation, but displayed few of the skeletal features of Marfan syndrome. Two of the 3 had a history of long-term hypertension, and such a history was suspected in the third patient. Brautbar et al. (2010) suggested that there are individuals with FBN1 mutations who have mild nonvascular involvement but significant aortic disease, in whom superimposed factors such as long-term hypertension may weaken the aortic wall and lead to the overt clinical phenotype. They proposed that all patients with descending thoracic aortic dissection be screened for connective tissue disease, with FBN1 sequencing in certain cases.

Yang et al. (2012) studied a 5-generation Chinese family in which 16 members were affected with isolated ectopia lentis and identified a heterozygous missense mutation in the FBN1 gene (R974C; 134797.0063) that segregated with disease. Yang et al. (2012) reviewed published reports and stated that 18 FBN1 mutations associated with isolated ectopia lentis had been found, 3 of which had also been found in association with Marfan syndrome in different families; they also noted that 15 of the mutations were cysteine substitutions.

Marfanoid-Progeroid-Lipodystrophy Syndrome

In a patient with marfanoid-progeroid-lipodystrophy syndrome (MFLS; 616914), Graul-Neumann et al. (2010) identified heterozygosity for a 2-bp deletion in exon 64 of the FBN1 gene (134797.0064) and excluded mutations in the TGFBR1 (190181) and TGFBR2 (190182) genes. The 27-year-old German woman fulfilled the clinical Ghent criteria for Marfan syndrome with 3 major features, including ectopia lentis, aortic dilatation, and dural ectasia, but also showed an extreme reduction in the amount of subcutaneous fat tissue since birth and had prominent facial lipodystrophy.

In a 20-year-old Irish man with Marfan lipodystrophy syndrome, Goldblatt et al. (2011) identified a heterozygous 20-bp deletion in exon 64 of the FBN1 gene (134797.0065) resulting in a frameshift and stop codon at the same relative location in the mRNA as that found by Graul-Neumann et al. (2010).

Horn and Robinson (2011) reported a 3.5-year-old girl who had progeroid facial signs of neonatal onset, large head with corresponding hydrocephaly, decreased subcutaneous fat, and tall stature at the end of infancy. Echocardiography revealed mild mitral valve prolapse. She did not fulfill the Ghent criteria for ocular or cardiovascular manifestations of Marfan syndrome at last examination, but her tall stature, arachnodactyly, and facial gestalt, which was similar to that of the patient reported by Graul-Neumann et al. (2010), prompted analysis of the FBN1 gene, in which a de novo heterozygous splice site mutation in intron 64 was identified (134797.0066).

In a 10-year-old Japanese girl with severe congenital lipodystrophy and neonatal progeroid appearance, accelerated growth in height with poor weight gain, and characteristic facial appearance as well as craniosynostosis, Takenouchi et al. (2013) identified heterozygosity for an 8-bp deletion in exon 64 of the FBN1 gene (134797.0069).

In a 16-year-old girl with Marfan lipodystrophy syndrome, Jacquinet et al. (2014) identified heterozygosity for a de novo splice site mutation in intron 64 of FBN1 (134797.0070). The authors noted that all reported mutations in MFLS patients result in a truncated mRNA predicted to encode a shorter protein with an altered protein sequence at the C terminus.

In 2 female patients with congenital partial lipodystrophy and a progeroid appearance, Romere et al. (2016) identified heterozygosity for truncating mutations in exon 64 of the FBN1 gene (see, e.g., 134797.0066). No additional clinical information was provided. Romere et al. (2016) also studied the C-terminal cleavage product of profibrillin, which they designated 'asprosin' after the Greek word for white, because of the reduction in subcutaneous white adipose tissue displayed by asprosin-deficient patients. Both of their patients showed lower levels of asprosin than would be expected with a heterozygous genotype, suggesting a dominant-negative effect.

Weill-Marchesani Syndrome 2

Faivre et al. (2003) analyzed the FBN1 gene in 2 families segregating autosomal dominant Weill-Marchesani syndrome (WMS2; 608328) that mapped to chromosome 15q21.1, and identified a heterozygous 24-bp deletion in 1 of the families (134797.0040).

Stiff Skin Syndrome

Loeys et al. (2010) sequenced the FBN1 gene in probands from 4 unrelated families with stiff skin syndrome (SSKS; 184900) and identified heterozygous missense mutations in each, all within exon 37 of the gene (see 134797.0050-134797.0053, respectively). Another patient who had a 'hybrid' phenotype of stiff skin syndrome with ectopia lentis was found to be heterozygous for a missense mutation in exon 38 of FBN1 (134797.0054). Loeys et al. (2010) noted that all of the stiff skin syndrome-associated mutations occurred within the fourth TGFB (TGFB1; 190180)-binding protein-like domain (TB4) of FBN1, which encodes the only RGD sequence in fibrillin-1, a motif that mediates cell-matrix interactions via integrin binding. In studies in human foreskin dermal fibroblasts (FS2 cells), the W1570C (134797.0050 and 134797.0051) and C1564S (134797.0052) mutations induced a marked loss of both attachment and spreading of FS2 cells compared to wildtype, suggesting impairment of interaction with alpha-V-beta-3 and possibly alpha-5-beta-1 integrins (see 193210 and 135620). Human endometrial stromal fibroblasts (hESF cells) also failed to attach or spread when plated on mutant substrates, and cultured dermal fibroblasts from patients with stiff skin syndrome showed reduced amounts of the activated (phosphorylated) form of focal adhesion kinase, an event mediated by the interaction of RGD ligands with integrins concentrated at focal adhesions. Loeys et al. (2010) suggested that FBN1 mutations that cause stiff skin syndrome can impair integrin binding and signaling.

Geleophysic Dysplasia 2 and Acromicric Dysplasia

In 29 patients with geleophysic dysplasia-2 (GPHYSD2; 614185) and 10 with acromicric dysplasia (ACMICD; 102370), Le Goff et al. (2011) performed exome sequencing followed by candidate gene analysis and identified heterozygosity for 16 different mutations in the FBN1 gene, respectively (see, e.g., 134797.0055-134797.0060), 2 of which were found both in patients with geleophysic dysplasia-2 and in patients with acromicric dysplasia. Both disorders are characterized by short stature, short hands and feet, joint limitations, and thickened skin, but geleophysic dysplasia patients also have cardiorespiratory involvement that often leads to early death. Le Goff et al. (2011) concluded that geleophysic dysplasia and acromicric dysplasia are clinically distinct but allelic conditions. All of the mutations identified in these patients were located in exons 41 and 42, encoding the TGFB-binding protein-like 5 domain (TB5) of FBN1, and none were found in 2,000 ethnically matched controls or in the Marfan mutation database. Microfibrillar network disorganization and enhanced TGFB signaling were consistent features in fibroblasts from both geleophysic and acromicric dysplasia patients.


Genotype/Phenotype Correlations

Palz et al. (2000) analyzed the terminal 7 exons (exons 59-65) of the FBN1 gene in 124 unrelated patients with MFS and identified 5 novel mutations. Their findings, together with the findings of the review by Collod-Beroud et al. (1998), showed that about 40% (8/20) of the mutations in exons 59-65 are associated with a mild phenotype characterized by a lack of aortic root pathology. In contrast, only about 7% of mutations reported in the remainder of the gene resulted in a mild phenotype without aortic root pathology, even when the mutation occurred in the same position in the cbEGF motif. The authors noted that observations suggesting that the N-terminal portion of FBN1 but not the C-terminal portion is required for incorporation into polymeric microfibrils (Lonnqvist et al., 1998) and for the homodimerization of fibrillin monomers (Trask et al., 1999) may provide an explanation for the proposed loose phenotype-genotype correlation.

Tiecke et al. (2001) analyzed exons 24-40 of the FBN1 gene by temperature-gradient gel electrophoresis in 124 unrelated patients with Marfan syndrome and identified 12 probable disease-causing mutations, 10 of which were novel. A recurrent mutation (G1013R; 134797.0036) in exon 24 was found in 2 unrelated patients with atypically severe clinical manifestations. Their results, together with those in other reports, showed that 12 of 14 missense mutations in patients with atypically severe MFS clustered in exons 24-32, suggesting a critical functional role for this region. Atypically severe MFS was characterized by cardiovascular complications requiring surgery in childhood as well as by abnormal face and ears, with or without congenital contractures. Missense mutations associated with neonatal MFS were found primarily in exons 25 and 26. Despite the clustering of mutations associated with neonatal and atypically severe MFS, mutations associated with classic MFS occurred in the same region. Based on these findings, Tiecke et al. (2001) concluded that there was no way of predicting whether a given mutation in exons 24-32 would be associated with classic, atypically severe, or neonatal MFS.

To correlate genotype with phenotype and define the subtype of fibrillinopathy caused by premature termination codon mutations, Schrijver et al. (2002) integrated genotype information and mRNA expression levels with clinical and biochemical phenotypes. By screening the entire FBN1 gene for mutations, they identified 34 probands with premature termination codon mutations. With the exception of 2 recurrent mutations, the nonsense and frameshift mutations were unique and spanned the entire FBN1 gene, from IVS2 to IVS63. Allele-specific RT-PCR reaction analyses revealed differential allelic expression in all studied samples, with variable reduction of the mutant transcript. Fibrillin protein synthesis and deposition into the extracellular matrix were studied by pulse-chase analysis of cultured fibroblasts. In most premature termination codon samples, synthesis of normal-sized fibrillin protein was approximately 50% of control levels, but matrix deposition was disproportionately decreased. Only 22 of 31 (71%) probands and 14 of 24 (58%) mutation-positive family members met clinical diagnostic criteria for MFS. The group with premature termination codon showed statistically significant differences in the frequency of individual signs, especially in the ocular manifestations, when compared with the previously reported study group of 44 individuals with FBN1 cysteine substitutions (Schrijver et al., 1999). Large-joint hypermobility was more common in the premature termination codon group, and lens dislocation and retinal detachment were less common. Schrijver et al. (2002) concluded that premature termination codon mutations have a major impact on the pathogenesis of type 1 fibrillinopathies and convey a distinct biochemical, clinical, and prognostic profile.

Loeys et al. (2004) undertook a study of the FBN1 gene in a cohort of 93 Marfan syndrome patients fulfilling the clinical diagnosis of the disorder according to the Ghent nosology. An initial mutation screening by CSGE/SSCP allowed identification of an FBN1 mutation in 73 patients. Then, sequencing of all exons of the FBN1 gene was performed in 11 mutation-negative patients, while in 9 others, DHPLC was used. This allowed identification of 7 and 5 additional mutations, respectively. Southern blot analysis revealed an abnormal hybridization pattern in 1 more patient. A total of 23 of the 85 mutations identified were reported by Loeys et al. (2004) for the first time. Phenotypic comparison of Marfan syndrome patients with cysteine-involving mutations versus premature termination mutations revealed significant differences in ocular and skeletal involvement. As described by Schrijver et al. (2002), PTC mutations appeared to be associated with more severe skeletal findings, whereas the cysteine substitution was associated with significantly greater incidence of ectopia lentis.

Rommel et al. (2005) analyzed the FBN1 gene in 116 patients with Marfan syndrome and identified 29 novel and 9 recurrent FBN1 mutations in 38 patients. Genotype-phenotype correlations showed a significantly lower incidence of ectopia lentis in patients who carried a mutation that led to a premature termination codon or a missense mutation without cysteine involvement in FBN1, as compared to patients whose mutations involved a cysteine substitution or splice site alteration.

Faivre et al. (2007) analyzed genotype/phenotype correlations in 1,013 probands with a pathogenic FBN1 mutation registered in the international FBN1 Universal Mutation Database (Collod-Beroud et al., 2003). A total of 803 pathogenic mutations were found in the 1,013 probands, including 114 recurrent mutations in 324 probands. Five hundred and forty-two of the 1,013 probands (54%) had ectopia lentis. The higher probability of ectopia lentis was found for patients with a missense mutation substituting or producing a cysteine, when compared with other missense mutations. Patients with an FBN1 premature termination codon had a more severe skeletal and skin phenotype than did patients with an in-frame mutation. Mutations in exons 24 through 32 were associated with a more severe and complete phenotype, including younger age at diagnosis of type I fibrillinopathy and higher probability of developing ectopia lentis, ascending aortic dilatation, aortic surgery, mitral valve abnormalities, scoliosis, and shorter survival; most of these results were replicated even when cases of neonatal MFS were excluded. Faivre et al. (2007) suggested that these correlations, found between different mutation types and clinical manifestations, might be explained by different underlying genetic mechanisms (dominant-negative vs haploinsufficiency) and by consideration of the 2 main physiologic functions of fibrillin-1 (structural vs mediator of TGF-beta signaling). Exon 24 through 32 mutations defined a group at high risk for cardiac manifestations associated with severe prognosis at all ages.

Faivre et al. (2007) pointed out the strong correlation between ectopia lentis and the presence of a mutation affecting a cysteine residue, and the fact that a main feature distinguishing the phenotype associated with mutations in TGFBR1 (190181) and TGFBR2 (190182) is the almost consistent absence of ocular involvement in the latter patients. Thus, it could be speculated that the functional aspect of fibrillin-1 that is altered in patients with ectopia lentis is not involved in TGF-beta signaling but is a structural function of the extracellular matrix. Correct cysteine localization and disulfide bonding appears to play an important role in the structural integrity of the suspensory ligament of the lens. On the other hand, the strong correlation between FBN1 premature termination codon (PTC) mutations and severe skeletal and skin phenotypes of a type associated also with TGFBR1/2 mutations suggests that a function or pathway common to fibrillin-1 and the TGF-beta type 1/2 receptors is altered in these patients. It could be speculated that haploinsufficiency for fibrillin-1 in bone and skin has a stronger affect on the TGF-beta signaling function of the protein than on its structural function--and thus that, in bone growth, fibrillin-1 acts as a mediator of TGF-beta signaling.

Blyth et al. (2008) reported 2 unrelated girls with severe early-onset Marfan syndrome who were found by MLPA dosage analysis to have exonic deletions in the FBN1 gene (see, e.g. 134797.0049). One patient was a somatic mosaic for the deletion. The authors suggested that Marfan patients with FBN1 deletions have a more severe phenotype than those with missense mutations.

Attanasio et al. (2008) identified FBN1 mutations in 75 (88%) of 85 patients with MFS and in 5 (36%) of 14 patients with a type I fibrillinopathies that did not meet the diagnostic criteria for MFS. Forty-six of 77 mutations were novel. The majority of missense mutations were within the calcium-binding EGF-like domains. There were preferential associations between cys-related missense mutations and ectopia lentis, and premature termination codon mutations and skeletal manifestations. In contrast to what had been reported in the literature, the cardiovascular system was severely affected also in patients carrying mutations in exons 1 to 10 and 59 to 65.

Faivre et al. (2009) analyzed the phenotypic characteristics of 198 probands (20%) with a mutation in exons 24 through 32 of the FBN1 gene from a series of 1,013 probands with an FBN1 mutation. Patients with mutations leading to a premature termination codon within exons 24 through 32 had a more severe phenotype with a significantly higher probability of developing ectopia lentis and mitral insufficiency compared to patients with in-frame mutations in the same region. Patients with a truncation mutation between exons 24 through 32 rarely displayed a neonatal or severe MFS presentation. However, those with mutations in exon 25, which encodes the eleventh EGF-like domain, had a higher probability of neonatal presentations and cardiovascular manifestations. Recurrent mutations were associated with high phenotypic heterogeneity ranging from neonatal to classical MFS phenotype.

Faivre et al. (2009) analyzed the clinical and molecular characteristics of 146 adult probands with known FBN1 mutations who did not fulfill the Ghent criteria for Marfan syndrome. The authors found at least 1 component of the Ghent nosology, insufficient alone to constitute a minor criterion, in 12 of 17 patients with isolated dilation of the ascending aorta and in 9 of 12 patients with isolated ectopia lentis. They stated that analysis of recurrent mutations and of affected family members of probands with only 1 major clinical criterion argued for a clinical continuum between such phenotypes and classic Marfan syndrome. Faivre et al. (2009) concluded that, using strict definitions, patients with FBN1 mutations and only 1 major clinical criterion or with only minor clinical criteria of 1 or more organ systems do exist, but represent only 5% of the adult cohort.

Stheneur et al. (2009) analyzed the FBN1 gene in 586 unrelated patients referred for molecular diagnosis, including 21 cases of neonatal MFS, 21 children with probable MFS, 105 adults with incomplete MFS, 266 adults with classic MFS, 21 adults with non-MFS, 15 patients with other diagnoses, and 137 patients excluded from statistical analysis. The mutation detection rate was 72.5% in probands with classic MFS, 58% in those referred for incomplete MFS, and only 14.3% for those referred as non-MFS. Recursive partitioning statistical analysis showed that, among the different variables tested, the most significant was the number of organ systems involved, and the second most significant was the presence of ectopia lentis. Stheneur et al. (2009) concluded that the best predictor for identification of an FBN1 mutation is the presence of features in at least 3 organ systems, combining 1 major and various minor criteria. They noted that the earlier recommendation of 2 systems involved with at least 1 major criterion represents the minimal criteria, because the mutation detection rate falls dramatically in probands not meeting those criteria.

Using DNA samples from 300 patients with clinical features of MFS or a related phenotype that had been previously screened by DHPLC with no mutations found in the FBN1 gene, Hilhorst-Hofstee et al. (2011) performed MLPA and identified 9 patients from 5 families with deletion of 1 entire FBN1 allele. A tenth patient with complete deletion of FBN1 was identified by cytogenetic analysis and array CGH. All of the patients had facial and skeletal features of MFS, and 7 of the 10 patients fulfilled the Ghent criteria; the 3 patients who did not present the full clinical picture of MFS were young (5, 8, and 13 years of age, respectively). Aortic root dilation was present in 6 patients, 2 of whom underwent surgical repair at relatively young ages. Hilhorst-Hofstee et al. (2011) concluded that complete loss of 1 FBN1 allele does not predict a mild phenotype, and that their findings supported the hypothesis that true haploinsufficiency can lead to the classic phenotype of Marfan syndrome.

In cultures of transiently transfected HEK293 cells, Jensen et al. (2015) demonstrated that MFS-associated substitutions involving domains TB4 and TB5 of FBN1 (C1564Y, C1719Y, and C1720Y) result in a loss of fibrillin-1 from the cell culture medium, whereas mutants associated with stiff skin syndrome (C1564S, 134797.0052; W1570C, 134797.0050 and 134797.0051) or the acromelic dysplasias (e.g., G1762S, 134797.0056) are secreted into the extracellular media. The stiff skin syndrome and acromelic dysplasia-associated mutants were further shown to incorporate into the microfibril network produced by fibroblasts in culture. Jensen et al. (2015) suggested that stiff skin syndrome and the FBN1-associated acromelic dysplasias, including geleophysic dysplasia-2 and acromicric dysplasia, result from postassembly changes in microfibril interactions, whereas MFS results from a loss of microfibrils. The authors proposed that aberrant TGFB signaling observed in each of the FBN1-associated diseases is due to different causes: in MFS, it is be due to loss of structural integrity in the fibrillin matrix, affecting TGFB activation through a change in the mechanical properties of tissues, whereas in stiff skin syndrome and the acromelic dysplasias, it more likely involves defective cell-surface interactions with microfibrils, resulting in TGFB dysregulation, fibrosis, and dermal accumulation of microfibril aggregates as a secondary response to an altered signaling program.

Takenouchi et al. (2013) reviewed 4 patients with Marfan lipodystrophy syndrome who all had mutations in exon 64 of FBN1. The authors noted that the frameshift mutations in 3 of the patients resulted in a common aberrant motif, ETEKHKRN, at the carboxyl termini of the transcripts, and suggested that this motif might be associated with the phenotype.

Variant Classification

Using FBN1-specific criteria and American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) 2015 guidelines for variant interpretation, Baudhuin et al. (2019) reanalyzed 674 FBN1 missense variants from 18 submitters to the ClinVar database. Of the 674 missense variants, 140 (20.8%) had more than 1 submitter, and 43 (30.7%) of the latter had discrepant classifications. Using gene-based knowledge, the authors were able to resolve all 43 missense variants that had discrepant multisubmitter ClinVar classifications, and also to revise variant calls in 150 (23.8%) of the remaining 631 FBN1 missense variants. Baudhuin et al. (2019) noted that many ClinVar entries did not contain substantive evidence to support their classification, and that variants without supporting data are of very little value. In the absence of phenotypic data, however, they concluded that variant classification can be refined using gene-based evidence.


Gene Therapy

There is a considerable body of evidence that many FBN1 mutant alleles lead to Marfan syndrome through a dominant-negative effect (Dietz and Pyeritz, 1995 Eldadah et al., 1995). Since this raises the possibility that reduction of the amount of mutant FBN1 might be a valid therapeutic approach for treating Marfan syndrome, Kilpatrick et al. (1996) designed and synthesized a trans-acting hammerhead ribozyme (see Cech and Bass, 1986) targeted to the 5-prime end of the human FBN1 mRNA. They noted that potential hammerhead ribozymes which possess a catalytic domain and flanking sequence complementary to a target mRNA, can cleave the target mRNA molecule in trans at a 3-base target sequence. Kilpatrick et al. (1996) delivered the ribozyme into cultured dermal fibroblasts by receptor-mediated endocytosis of a ribozyme-transferrin-polylysine complex. They noted that successful delivery of the ribozyme reduced both cellular FBN1 mRNA and the deposition of fibrillin in the extracellular matrix. Kilpatrick et al. (1996) concluded that the sensitivity of hammerhead ribozymes to mismatches between ribozyme and target sequences supports the feasibility of designing ribozymes to target mutant FBN1 alleles.

Antisense technologies for the targeted inhibition of gene expression could provide an effective strategy for the management of inherited disorders with dominant-negative or gain-of-function pathogenetic mechanisms, for the suppression of oncogenes, or for the control of a variety of infectious agents. In situ expression of antisense complementary RNA (cRNA) has many theoretical and practical advantages over methods based on the exogenous administration of synthetic oligodeoxynucleotides which have a propensity for producing non-sequence-specific biologic effects. For in vivo therapeutic applications, foremost among these advantages is the potential for enduring activity. Many naturally occurring cRNAs with well-documented regulatory functions have been described in prokaryotes. All are characterized by stable stem-loops that encompass or flank the targeting sequence, with the 3-prime loop generally having a high GC content. These structures are believed to enhance stability of the targeting molecules by conferring resistance to the activity of exonucleases. Montgomery and Dietz (1997) fashioned an antisense expression construct to mimic selective properties of naturally occurring antisense RNAs in prokaryotes for efficient inhibition of gene expression by in situ-expressed recombinant molecules in mammalian cells. Prokaryotic regulatory transcripts are expressed at high levels and have hairpin structures at their termini, features reminiscent of small nuclear RNAs (snRNAs) which are abundant and stable in the nucleus of all mammalian cells. Montgomery and Dietz (1997) substituted a sequence complementary to fibrillin-1 mRNA, interrupted in its center by a hammerhead ribozyme, for the Sm protein binding site between the stem-loop structures of U1 snRNA. Expression of the chimeric antisense RNA resulted in dramatic inhibition of expression of fibrillin-1 message and protein in stably transfected cultured cells. The inhibitory effect was localized to the nucleus. They suggested that the biologic properties of U1 snRNA may provide a widely applicable vehicle for the in vivo delivery of antisense targeting sequences. Use of this approach in Marfan syndrome would allow the application of a single strategy to all patients despite allelic heterogeneity.


Animal Model

'Tight-Skin' Mouse

Green et al. (1976) described a novel mouse mutant, 'tight-skin' (Tsk). Heterozygotes had tight skin with marked hyperplasia of subcutaneous loose connective tissue. Increased growth of cartilage and bone was a feature. Tendons were small with hyperplasia of the sheaths. Homozygotes died in utero. Growth hormone was normal. The authors speculated that the mutation may cause defective cell receptors with high affinity for a somatomedin-like factor promoting growth of connective tissue.

Muryoi et al. (1991) showed that Tsk mice spontaneously produce anti-topoisomerase I antibodies, which are characteristically found only in patients with progressive systemic sclerosis (181750) but not in patients with the CREST syndrome, a systemic sclerosis-related disorder. The autoantibodies produced in the tight-skin mouse are encoded primarily by heavy-chain variable genes from the J558 family. Kasturi et al. (1994) showed that the J558 genes encoding these antibodies are not derived from a selected germline gene(s) or a single subfamily but rather from genes belonging to diverse J558 subfamilies. All the results strongly suggested that the establishment of the autoimmune repertoire is mediated by V(H)-gene-dependent selection of B cells, though the contribution of an antigen-mediated selection mechanism could not be ruled out.

Siracusa et al. (1993) localized the Tsk mutation with respect to known molecular markers on mouse chromosome 2. Everett et al. (1994) showed that Tsk is closely linked to the gene for bone morphogenetic protein-2A (112261). Using an interspecific backcross, Doute and Clark (1994) carried out positional cloning of Tsk and determined linkage to several genetic markers in the following order on mouse chromosome 2: pa-B2m-Tsk-Fbn-1-II-1a-a.

The Tsk locus maps to a region on chromosome 2 that includes a segment that is syntenic with human chromosome 15 (Doute and Clark, 1994). Since the microfibrillar glycoprotein gene fibrillin-1 is located on human 15q, it became a candidate for the Tsk mutation in the mouse. Siracusa et al. (1996) demonstrated that the Tsk chromosome harbors a 30- to 40-kb genomic duplication within the Fbn1 gene that results in a larger than normal in-frame Fbn1 transcript. The findings provided possible explanations for the phenotypic features of Tsk/+ mice and the lethality of Tsk/Tsk embryos. Siracusa et al. (1996) noted that the Tsk mouse has been used as a model for several human diseases, including stiff skin syndrome (SSKS; 184900).

Kielty et al. (1998) examined the consequences of the mouse Tsk mutation. Dermal fibroblasts from heterozygous mice synthesized and secreted both normal fibrillin and a mutant oversized fibrillin in comparable amounts, and Tsk fibrillin-1 was stably incorporated into cell layers. Studies by several methods indicated that Tsk fibrillin-1 polymerizes and becomes incorporated into a discrete population of beaded microfibrils with altered molecular organization.

The protein encoded by the mutant Tsk gene is larger (418 kD) than the normal (350 kD) fibrillin protein. Gayraud et al. (2000) found that mice compound heterozygous for the Tsk mutation and hypomorphic Fbn1 alleles displayed both Tsk and MSF traits. Further studies suggested that bone and lung abnormalities of Tsk/+ mice are due to copolymerization of mutant and wildtype molecules into functionally deficient microfibrils. Vascular complications were thought to be absent in these animals because the level of functional microfibrils does not drop below the critical threshold. Indirect in vitro evidence suggested that a potential mechanism for the dominant-negative effects of incorporating Tsk fibrillin-1 into microfibrils is increased proteolytic susceptibility conferred by the duplicated Tsk region.

Saito et al. (2002) found that B cells of Tsk/+ mice, a model for human systemic sclerosis, had decreased IgM expression, enhanced serum IgG production, spontaneous autoantibody production, and enhanced Cd19 (107265) tyrosine phosphorylation, Vav (164875) phosphorylation, and Lyn (165120) kinase activity. Tsk/+ mice deficient in Cd19 expression showed decreased skin fibrosis, upregulated surface IgM expression, abrogation of hypergammaglobulinemia and autoantibody production, and inhibition of Il6 (147620) production. Saito et al. (2002) concluded that chronic B-cell activation resulting from augmented Cd19 signaling in Tsk/+ mice leads to skin sclerosis and autoimmunity, possibly through overproduction of Il6.

Gerber et al. (2013) generated 2 Fbn1-targeted mouse models of stiff skin syndrome (184900), one harboring a W1572C mutation, which is equivalent to human W1570C (134797.0050 and 134797.0051), and the other harboring a D1545E mutation, which eliminates the RGD motif needed to mediate cell-matrix interactions by binding to cell surface integrins. Gerber et al. (2013) showed that mouse lines harboring these mutations recapitulated aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the profibrotic cytokine transforming growth factor-beta (TGFB). Mutant mice showed skin infiltration of proinflammatory immune cells, including plasmacytoid dendritic cells, T helper cells, and plasma cells, as well as autoantibody production. These findings were normalized by integrin-modulating therapies or TGFB antagonism. Gerber et al. (2013) concluded that the results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programs and highlight new therapeutic strategies for systemic sclerosis (181750).

Marfan Syndrome Models

It was believed that microfibrils, of which fibrillin-1 is the major constituent, regulated elastic fiber formation by guiding tropoelastin deposition during embryogenesis and early postnatal life. Hence, vascular disease in Marfan syndrome was thought to result when FBN1 mutations precluded elastic fiber maturation by disrupting microfibrillar assembly. However, Pereira et al. (1997) performed a gene-targeting experiment in mice that indicated that fibrillin-1 microfibrils are predominantly engaged in tissue homeostasis rather than elastic matrix assembly. This finding, in turn, suggested that aortic dilation is due primarily to the failure by the microfibrillar array of the adventitia to sustain physiologic hemodynamic stress, and that disruption of the elastic network of the media is a secondary event.

A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax). To investigate the pathogenesis of genetically imposed emphysema, Neptune et al. (2003) analyzed the lung phenotype of mice deficient in fibrillin-1 (Pereira et al., 1997). Lung abnormalities were evident in the immediate postnatal period and were manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 developed destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. Neptune et al. (2003) showed that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-beta-1 (TGFB1; 190180) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta by means of a TGF-beta-neutralizing antibody attenuated apoptosis and rescued alveolar septation in vivo. These data indicated that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease. Kaartinen and Warburton (2003) discussed the general implications of the finding that fibrillin controls TGF-beta activation.

Ng et al. (2004) examined mitral valves from fibrillin-1 null mice and found postnatally acquired alterations in architecture that correlated both temporally and spatially with increased cell proliferation, decreased apoptosis, and excess TGF-beta activation and signaling. TGF-beta antagonism in vivo rescued the valve phenotype. Expression analyses identified increased expression of numerous TGF-beta-related genes that regulate cell proliferation and survival. Ng et al. (2004) suggested that TGF-beta is a mediator of myxomatous mitral valve disease.

A dominant-negative mechanism has been inferred for the pathogenesis of Marfan syndrome based upon dominant inheritance, multimerization of monomers to form microfibrils, and the dramatic paucity of matrix-incorporated fibrillin-1 seen in heterozygous patient samples. Judge et al. (2004) presented evidence for a critical role of haploinsufficiency in the pathogenesis of Marfan syndrome. Yeast artificial chromosome-based transgenesis was used to overexpress the disease-associated cys1663-to-arg mutant form of human fibrillin-1 (C1663R; 134797.0006) on a normal mouse background. The mice failed to show any abnormalities of cellular or clinical phenotype despite regulated overexpression of mutant protein in relevant tissues and developmental stages and despite direct evidence that mouse and human fibrillin-1 interact with high efficiency. Immunostaining with a human-specific monoclonal antibody demonstrated that mutant fibrillin-1 can participate in productive microfibrillar assembly. Use of homologous recombination to generate mice heterozygous for a missense mutation comparable to C1663R (i.e., C1039G) revealed impaired microfibrillar deposition, skeletal deformity, and progressive deterioration of aortic wall architecture, comparable to characteristics of the human condition. The data were considered consistent with a model that invokes haploinsufficiency for wildtype fibrillin-1, rather than production of mutant protein, as the primary determinant of failed microfibrillar assembly. In keeping with this model, introduction of a wildtype FBN1 transgene on a heterozygous C1039G background rescued aortic phenotype. In commenting on the work of Judge et al. (2004), Byers (2004) reviewed the evidence that fibrillin is more than a structural protein. The interrelationship with TGF-beta was reviewed with a diagram adapted from Kaartinen and Warburton (2003). Byers (2004) suggested that TGF-beta blockade may be used in preference to beta-adrenergic blockade as a more effective treatment of many aspects of Marfan syndrome.

Using the Fbn1(mgR/mgR) mouse model of Marfan syndrome, Cook et al. (2014) determined that dilated cardiomyopathy (DCM) in fibrillin-1-deficient mice is a primary manifestation of extracellular matrix (ECM)-induced abnormal mechanosignaling by cardiomyocytes. MFS mice displayed spontaneous emergence of an enlarged and dysfunctional heart, altered physical properties of myocardial tissue, and biochemical evidence of chronic mechanical stress, including increased AGTR1 (106165) signaling and abated focal adhesion kinase (FAK; 600758) activity. Partial fibrillin-1 gene inactivation in cardiomyocytes was sufficient to precipitate DCM in otherwise phenotypically normal mice. Consistent with abnormal mechanosignaling, normal cardiac size and function were restored in MFS mice treated with an AGTR1 antagonist and in MFS mice lacking AGTR1 or beta-arrestin-2 (ARB2; 107941), but not in MFS mice treated with an angiotensin-converting enzyme (ACE; 106180) inhibitor or lacking angiotensinogen. Conversely, Cook et al. (2014) found that DCM associated with abnormal AGTR1 and FAK signaling was the sole abnormality in mice that were haploinsufficient for both fibrillin-1 and beta-1 integrin (ITGB1; 135630). The authors concluded that these findings implicated fibrillin-1 in the physiologic adaptation of cardiac muscle to elevated workload.

Marfanoid-Progeroid-Lipodystrophy Syndrome Models

Duerrschmid et al. (2017) generated C57Bl/6 mice that were heterozygous for a mutation that results in skipping of Fbn1 exon 65, analogous to a mutation (134797.0066) found in patients with Marfan lipodystrophy syndrome, and observed a phenocopy of the human disorder. The mutant mice displayed extreme leanness compared to sex-matched littermates, and DEXA scan revealed reductions in both fat mass and lean mass, with no significant change in body length. When exposed to severe diabetogenic and obesogenic stress, the mutant mice were completely protected from both obesity and diabetes. Similar to the human disorder, the mutant mice exhibited hypophagia as well as a reduction in energy expenditure. In addition, the activity of known orexigenic AgRP+ neurons within the hypothalamus was significantly lower in the mutant mice compared to wildtype mice. A single subcutaneous dose of the C-terminal cleavage product of profibrillin, asprosin, was sufficient to rescue the hypophagia phenotype completely, thus demonstrating that the hypophagia was due to asprosin deficiency rather than an indirect effect of mutated Fbn1. Tagged recombinant asprosin injected intravenously into rats was detected 1 hour later in their cerebrospinal fluid, indicating that plasma asprosin crosses the blood-brain barrier. Treatment with an asprosin-specific antibody significantly reduced intake in wildtype mice of a different genetic background (KK strain), but asprosin neutralization had no effect on food intake in Agouti yellow mice, indicating that asprosin-mediated appetite stimulation requires an intact melanocortin pathway (see POMC, 176830). In Lepr-db/db obese mice, which have a mutation in the leptin receptor (601007), immunologic neutralization of asprosin over 5 days showed reduced food intake and an improvement in body weight.


ALLELIC VARIANTS 70 Selected Examples):

.0001   MARFAN SYNDROME, SEVERE CLASSIC

FBN1, ARG1137PRO
SNP: rs137854456, gnomAD: rs137854456, ClinVar: RCV000017883

In 2 unrelated girls, one Caucasian and one black, with severe classic Marfan syndrome (MFS; 154700), Dietz et al. (1991) found a G-to-C transversion at nucleotide 3410, which converted codon 1137 from CGC (arginine) to CCC (proline). In both cases the mutation was heterozygous and represented a de novo event. After the first affected patient was found, allele-specific oligonucleotides (ASOs), specific for the normal and mutant alleles, were used to screen PCR-amplified genomic DNA from 19 additional patients with sporadic disease, their parents, and an affected individual from each of 24 families with the Marfan syndrome. The second de novo occurrence of R1137P was observed in one of the patients with sporadic disease. None of the other patients showed abnormality. The change in this disorder is nonconservative, replacing a basic amino acid with the nonpolar alpha-amino acid proline. The mutation occurs in an 'EGF-like' repeat, which has homology in Drosophila and C. elegans, suggesting that this is a functionally significant region of the protein. R1137P also occurs at a CpG dinucleotide but does not involve the C-to-T transition usually associated with such mutational 'hotspots.' Recurrent de novo mutation that is not a transition at a CpG dinucleotide has been found also in the factor VIII gene (300841). Although R1137P was the only recurrent mutation identified to that date, its rarity was indicated by the failure to find any example among 180 unrelated Marfan syndrome patients distributed in 3 reported studies (Tynan et al., 1993). This mutation was previously known as ARG239PRO.


.0002   MARFAN SYNDROME, MILD VARIABLE

FBN1, CYS2307SER
SNP: rs137854457, ClinVar: RCV000017884, RCV000663912

In a family in which multiple members in several generations had the Marfan syndrome (MFS; 154700) with wide variability in the age of onset, organ-system involvement and clinical severity, Dietz et al. (1992) found a cysteine-to-serine substitution at codon 2307 (C2307S) in an EGF-like motif from one fibrillin allele. Twenty individuals were investigated. All 4 living and clinically affected persons carried the mutation. Some affected adults were unaware of their status before the molecular diagnosis. This mutation was previously known as CYS1409SER.


.0003   MARFAN SYNDROME

FBN1, 366-BP DEL
ClinVar: RCV000017885

Screening 20 unrelated patients with Marfan syndrome (MFS; 154700) for mutations in fibrillin cDNA by single-strand conformation polymorphism analysis, Kainulainen et al. (1992) found 2 with mutations in heterozygous form that resulted in a shortened fibrillin polypeptide. The first mutation was a large in-frame deletion of 366 bases of the fibrillin mRNA, now known to encode exons 60-62, that resulted in a truncated but secreted polypeptide found in the fibroblast culture of the patient. The patient was a 48-year-old man with cardiovascular, eye, and skeletal features of the Marfan syndrome. He was a member of a 3-generation English pedigree, none of whom had ectopia lentis. A brother had had mitral valve replacement at 39 years of age and died suddenly at age 44. A sister also had severe mitral valve prolapse and moderate aortic root dilatation.


.0004   MARFAN SYNDROME

FBN1, G8268A, TRP2756TER
SNP: rs267606796, ClinVar: RCV000017886, RCV001851898

In a 55-year-old Finnish man with Marfan syndrome (MFS; 154700) manifested by dislocated lenses, retinal detachment, aneurysm of the ascending aorta with aortic regurgitation, and typical skeletal features, Kainulainen et al. (1992) identified a G-to-A transition at nucleotide 8268, predicting premature termination by 116 amino acids. By molecular studies in the family and by family history, the patient appeared to be a sporadic case. This mutation was previously designated as TRP1858TER.


.0005   MARFAN SYNDROME

FBN1, CYS1249SER
SNP: rs137854458, ClinVar: RCV000017887, RCV002345247

In a patient with childhood presentation of sporadic Marfan syndrome (MFS; 154700), Dietz et al. (1992) found a heterozygous 3746G-C transversion in the FBN1 gene, resulting in a cys1249-to-ser (C1249S) substitution. The patient had ectopia lentis, long-bone overgrowth, scoliosis, mitral valve prolapse, and aortic root dilatation. This mutation was previously designated as CYS351SER.


.0006   MARFAN SYNDROME

FBN1, CYS1663ARG
SNP: rs137854459, ClinVar: RCV000017888

By SSCP analysis of cDNA, Dietz et al. (1992) detected an abnormally migrating band unique to the sample of the patient with the Marfan syndrome (MFS; 154700). Direct sequencing revealed a T-to-C transition at nucleotide 4987 in 1 FBN1 allele causing the substitution of arginine for cysteine at codon 1663. The patient was adopted as an infant and the medical history for his biologic parents was not available. He had classic and severe features of the Marfan syndrome which presented in early childhood, necessitating surgical intervention for scoliosis and aortic root dilatation. He also had ectopia lentis. This mutation was previously designated as CYS765ARG.


.0007   MARFAN SYNDROME

FBN1, CYS2221SER
SNP: rs137854460, ClinVar: RCV000017889

In a patient with Marfan syndrome (MFS; 154700) with classic and severe involvement of the ocular, skeletal, and cardiovascular systems, Dietz et al. (1992) found an abnormally migrating fragment on SSCP analysis and showed by direct sequencing a G-to-C transversion in 1 FBN1 allele at nucleotide 6662 causing the substitution of serine for cysteine at codon 2221. This mutation was previously designated as CYS1323SER.


.0008   MARFAN SYNDROME

FBN1, TYR2113TER, EX51DEL
SNP: rs267606797, gnomAD: rs267606797, ClinVar: RCV000017892, RCV000701293

In a patient with typical Marfan syndrome (MFS; 154700), Dietz et al. (1993) found deletion of exon 51 in the FBN1 cDNA. In the genomic DNA, they demonstrated a T-to-G transversion in 1 allele at position 26 in exon 51. The corresponding amino acid alteration was a substitution of a termination codon for tyrosine at codon 2113 (Y2113X) in the characterized coding sequence of FBN1. This unusual finding represented the skipping of a constitutive exon containing a nonsense mutation. Similar results were observed for 2 nonsense mutations in the OAT gene in patients with gyrate atrophy (see 258870.0036 and 258870.0037). This mutation was previously designated as TYR1215TER. See also Dietz and Kendzior (1994).

Caputi et al. (2002) presented evidence, based on both in vivo and in vitro experiments, that the skipping of exon 51 that occurs with this mutation is due to the disruption of an SC35-dependent exonic splicing enhancer (ESE) within exon 51. In addition, this mutation induces nonsense-mediated decay (NMD), which degrades the normally spliced mRNA in the patient's cells. In contrast to NMD, nonsense-mediated alternative splicing (NAS) does not require translation and is therefore not affected by inhibitors of translation. Maquat (2002) noted that ESE sequences are present in constitutively and alternatively spliced exons, are distinct from the splice site sequences, and are required for efficient splicing of certain exons. Maquat (2002) compared NAS with NMD of mRNA.


.0009   MARFAN SYNDROME

FBN1, ASN2144SER
SNP: rs137854461, ClinVar: RCV000017893, RCV000524502, RCV001170530, RCV001836710

In a 20-year-old man with skeletal and cardiac features of Marfan syndrome (MFS; 154700) but no ocular manifestations, Hewett et al. (1993) found heterozygosity for an A-to-G transition at position 6431 that changed the AAT codon for asparagine-2144 to the serine codon AGT. The same clinical features and mutation were shared by the father and the only sib. Hewett et al. (1993) suggested that the asn2144-to-ser mutation probably affects only the calcium-binding activity of the EGF-like module rather than its overall structure. This in turn suggested that the arg1137-to-pro (134797.0001) and cysteine substitutions found in other Marfan syndrome cases may exert their effect on phenotypes through interference with calcium binding rather than by any other mechanism. This mutation was previously designated as ASN1246SER.


.0010   MARFAN SYNDROME

FBN1, ASN548ILE
SNP: rs137854462, ClinVar: RCV000017894, RCV003764582

In a patient with classic and severe Marfan syndrome (MFS; 154700), Dietz et al. (1993) demonstrated an N548I missense mutation by SSCP analysis. This mutation was previously designated ASN-351ILE.

Reinhardt et al. (2000) showed that the N548I and glu1073-to-lys (E1073K; 134797.0038) mutations render the polypeptide significantly more susceptible to proteolytic degradation by a variety of proteases as compared with their wildtype counterparts.


.0011   MARFAN SYNDROME

FBN1, ASP723ALA
SNP: rs137854463, ClinVar: RCV000017895, RCV002426510, RCV003764583

In a patient with classic and severe Marfan syndrome (MFS; 154700), Dietz et al. (1993) demonstrated a D723A missense mutation by SSCP analysis. This mutation was previously designated as ASP-176ALA.


.0012   MASS SYNDROME

FBN1, 4-BP INS, NT5138
SNP: rs1131692049, ClinVar: RCV000017896

In a patient with mitral valve prolapse, extreme dolichostenomelia, early myopia, and striae distensae but no specific features of Marfan syndrome, Dietz et al. (1993) found insertion of 4 nucleotides, TTCA, after nucleotide 5138 resulting in a frameshift. The abnormality was a tandem insertion and was detected by SSCP analysis. The aortic root dimension in this patient was at the upper limit of normal when standardized to body surface area. The patient's mother and brother had moderately tall stature (without long-bone overgrowth) and myopia or mitral valve prolapse, respectively, but no specific features of the Marfan syndrome. The disorder in the patient satisfies the characteristics of the MASS phenotype (604308) as described by Glesby and Pyeritz (1989). Studies in the family showed that the mutation was de novo in the proband. Dietz et al. (1993) demonstrated extreme reduction in the amount of mutant allele transcript compared to that from the wildtype allele as opposed to the findings in missense mutations. These data, taken in connection with the mild clinical manifestations associated with the nonsense mutations, support a dominant-negative mechanism for the pathogenesis of the Marfan syndrome resulting from missense mutations. Dietz et al. (1993) presented a figure (their Fig. 6) to illustrate how they thought the dominant-negative model explains either severe or mild clinical manifestations. This mutation was previously designated as 2444INS4.


.0013   MARFAN SYNDROME

FBN1, 83-BP DEL
SNP: rs794728213, ClinVar: RCV000017897, RCV000181502, RCV001389970

By SSCP analysis, Dietz et al. (1993) found deletion of 83 bp (comprising exon 2) creating a frameshift and a premature TAG stop codon in exon 4 in a patient with classic and severe manifestations of Marfan syndrome (MFS; 154700) in the ocular, skeletal, and cardiovascular systems. The mutation was thought to be de novo. The deletion was the result of a G-to-A transition at position +1 resulting in skipping of the upstream exon. It is noteworthy that the deletion in this patient was associated with severe disease despite expression of only the extreme 5-prime sequence from the mutant allele. These data suggest that the amino terminal region of fibrillin is critical to microfibrillar assembly and, in isolation, can participate in a dominant-negative fashion with wildtype monomer.


.0014   MARFAN SYNDROME

FBN1, IVS54DS, G-C, +1, 123-BP DEL
SNP: rs869025419, gnomAD: rs869025419, ClinVar: RCV000017898

In a 4-generation kindred with Marfan syndrome (MFS; 154700), Godfrey et al. (1993) detected in affected members a deletion of 123 bp by RT-PCR amplification of fibrillin mRNA. The deletion corresponded to an exon (exon 54) encoding an epidermal growth factor-like motif. The deleted region began at position 6664. Examination of genomic DNA showed a G-to-C transversion at the +1 consensus donor splice site. In this family, genetic linkage analysis with fibrillin-specific markers had been used to establish the prenatal diagnosis at 11 weeks of gestation. In this same family, Rantamaki et al. (1995) made the prenatal diagnosis of Marfan syndrome by identification of the mutation in a chorionic villus sample.


.0015   ECTOPIA LENTIS 1, ISOLATED, AUTOSOMAL DOMINANT

FBN1, GLU2447LYS
SNP: rs137854464, gnomAD: rs137854464, ClinVar: RCV000017899, RCV000417099, RCV000422790, RCV000695313, RCV000844887, RCV002381253

Kainulainen et al. (1994) described an E2447K mutation in a British 4-generation family in which 3 living subjects suffered from dominantly inherited ectopia lentis (ECTOL1; 129600). It was stated that the phenotype also included 'some skeletal manifestations, but no symptoms at all in the cardiovascular system.' The mutation was detected in the DNA of all subjects with dislocated lenses, as well as in the DNA of 3 other members of the family with only skeletal manifestations of the disorder.

In a 4-generation family with predominant ectopia lentis and only mild skeletal features of the Marfan syndrome but no sign of cardiovascular abnormality, Lonnqvist et al. (1994) found a G-to-A transition at nucleotide 7339, resulting in the substitution of lysine for glutamic acid at codon 2447 (E2447K) of fibrillin cDNA. It appears that this is the same family as that reported by Kainulainen et al. (1994). This mutation was previously designated as GLU1549LYS.

Comeglio et al. (2007) analyzed the FBN1 gene in the family previously studied by Lonnqvist et al. (1994) and identified the E2447K mutation in a 51-year-old affected individual who exhibited major ocular and cardiovascular manifestations as well as minor skeletal involvement. In Table 1, Comeglio et al. (2007) designated this patient as having Marfan syndrome (MFS; 154700).


.0016   MARFAN SYNDROME, NEONATAL

FBN1, CYS1074ARG
SNP: rs137854465, ClinVar: RCV000017900

In a Swiss infant with a severe, neonatal form of Marfan syndrome (MFS; 154700) (Raghunath et al., 1993), Kainulainen et al. (1994) found a C1074R mutation in the FBN1 gene. As expected, neither of the parents carried the mutation. This mutation was previously designated as CYS176ARG.


.0017   MARFAN SYNDROME

FBN1, ARG2776TER
SNP: rs137854466, gnomAD: rs137854466, ClinVar: RCV000017901, RCV000181630, RCV000631918, RCV001374806, RCV002310993

In a 57-year-old patient with Marfan syndrome (MFS; 154700) and her 27-year-old son, Hayward et al. (1994) found an arg2776-to-ter mutation predicted to result in premature termination of the FBN1 polypeptide chain by 96 amino acids. This mutation was previously designated as ARG1878TER.


.0018   MARFAN SYNDROME, ATYPICAL

FBN1, ARG122CYS
SNP: rs137854467, ClinVar: RCV000017902, RCV000029732, RCV000181647, RCV000626614, RCV001000178, RCV001201375, RCV001798007, RCV002496395

Stahl-Hallengren et al. (1994) described an unusual mutation in the FBN1 gene in a family with several members affected with an atypical form of Marfan syndrome (MFS; 154700). The proband was 21 years old when he was referred to a rheumatologist because of pain in the hands during motion and episodes of knee joint effusions. There were no joint deformities, no scoliosis, and no cardiac symptoms. He had had spherophakia and lens dislocation since childhood. In his family, 8 members had lens dislocation and 7 of these underwent echocardiography with particular attention to aortic root dimensions and valvular function. No sign of aortic root dilatation, mitral valve prolapse, or other kind of cardiac involvement was observed either on physical examination or on echocardiography and there was no history of sudden deaths in the family. One or several episodes of knee joint effusion with moderate pain had occurred in 5 individuals. These episodes may have been related to moderate physical activity. Physical examination did not reveal ongoing joint effusion or other signs of synovitis in any of the family members. Five of the individuals with ectopia lentis had flexion contractures of the fifth proximal interphalangeal joint, whereas none of the other family members had this. The upper segment/lower segment ratio of the affected individuals was within the range characteristic of the Marfan syndrome. Linkage analysis with an informative marker in the vicinity of the fibrillin locus on chromosome 15, namely G113, revealed a lod score of 2.4 with no recombinations between the disorder and the marker. By using an automated sequenator in the screening of specific regions of FBN1 cDNA prepared from the cultured fibroblasts of the one affected family member, Stahl-Hallengren et al. (1994) identified a C-to-T transition at nucleotide 364. This mutation substituted a cysteine for arginine-122 (R122C). The mutation was confirmed in genomic DNA of the proband by use of the solid-phase minisequencing technique. This technique was also used to establish that all affected members of the family carried the same mutation, whereas unaffected members did not have the mutation. Furthermore, none of 60 Marfan patients or 60 healthy controls analyzed was shown to carry this mutation. The fibrillin polypeptide is made up of 47 repetitive EGF-like repeats interspersed by other motifs. Most of the EGF-like motifs have calcium-binding properties; however, 3 of them located close to the amino-terminal end of the fibrillin polypeptide exhibit the characteristic 6-cysteine pattern, but lack the putative calcium-binding consensus sequence. The R122C mutation in this family occurred in the second of these 3 non-calcium-binding EGF-like motifs and resulted in an extra cysteine just before the conserved second cysteine in this motif. Stevenson et al. (1982) gave the clinical description of 2 families with ectopia lentis in association with dolichostenomelia and joint stiffness.


.0019   MARFAN SYNDROME, NEONATAL

FBN1, IVS31AS, A-T, -2
SNP: rs387906547, ClinVar: RCV000017903

In a patient with the severe neonatal form of Marfan syndrome (MFS; 154700) leading to death at 3 months of age due to cardiac and respiratory failure, Wang et al. (1995) found missplicing of exon 31 of the FBN1 gene due to an A-to-T transversion at the -2 position of the consensus acceptor splice site. Exon 31 encodes an EGF-like calcium binding domain. This was a de novo mutation case; the father was 37 years old.


.0020   MARFAN SYNDROME, NEONATAL

FBN1, IVS32DS, G-A, +1
SNP: rs387906548, ClinVar: RCV000017904, RCV000659538

Wang et al. (1995) found a missplicing mutation of exon 32 in a female infant with severe neonatal Marfan syndrome (MFS; 154700). The infant died at 5 months of age due to cardiac failure. A G-to-A transition at the +1 position of the donor splice site of intron 32 was identified. The patient represented a new mutation.


.0021   MARFAN SYNDROME, MILD

FBN1, GLY1127SER
SNP: rs137854468, ClinVar: RCV000017905, RCV000590660, RCV000631963

Francke et al. (1995) identified disease of the ascending aorta, ranging from mild aortic root enlargement to aneurysm and/or dissection, in 10 individuals of a kindred, none of whom had classic Marfan syndrome (MFS; 154700). The proband was a 72-year-old woman, 174.5 cm tall, who was referred because of aortic root aneurysm, aortic regurgitation, and mitral valve prolapse. A brother had been discovered to have a type A aortic dissection with normal aortic valve and normal sinus of Valsalva at the age of 65 and successful surgical repair was performed. Single-strand conformation analysis of the entire FBN1 cDNA of an affected family member demonstrated a G-to-A transition at nucleotide 3379, predicting a gly1127-to-ser substitution. The glycine in this position is highly conserved in EGF-like domains of FBN1 and other proteins. The mutation was present in 9 of 10 affected family members and in 1 young unaffected member, but was not found in other unaffected members, in 168 chromosomes from normal controls, or in 188 chromosomes from other individuals with Marfan syndrome or related phenotypes. FBN1 intragenic marker haplotypes ruled out the possibility that the other allele played a significant role in modulating the phenotype in this family. Pulse-chase studies revealed normal fibrillin synthesis but reduced fibrillin deposition into the extracellular matrix in cultured fibroblasts from a gly1127-to-ser carrier. Francke et al. (1995) suggested that mutations such as this may disrupt EGF-like domain folding less dramatically than do substitutions of cysteine or other amino acids important for calcium-binding that cause classic Marfan syndrome. They suggested that the findings in this family were consistent with an emerging recognition that FBN1 alterations produce a spectrum of connective tissue disorders that extend beyond the classic Marfan phenotype and for which the term fibrillinopathy has been proposed.


.0022   MARFAN SYNDROME

FBN1, CYS1223TYR
SNP: rs137854469, ClinVar: RCV000017906, RCV000242083

Hewett et al. (1994) described a patient with Marfan syndrome (MFS; 154700) who was heterozygous for a G-to-A transition at nucleotide 3952 in the FBN1 gene that resulted in a cys1223-to-tyr (C1223Y) substitution.

In a 7-year-old girl with typical ocular, skeletal, and cardiovascular features of Marfan syndrome but with additional features suggesting the diagnosis of Shprintzen-Goldberg syndrome (SGS; 182212), including hypotonia, scaphocephaly with craniosynostosis, low-set anomalous ears, hyperelastic skin, diastasis recti, vertical talus, and mental retardation, Dietz et al. (1995) found a G-to-A transition at nucleotide 3668, resulting in a C1223Y substitution within one of the repetitive EGF-like domains within fibrillin-1. The mutation occurred as a de novo event in heterozygous state and was not detected in over 100 chromosomes from control individuals. Although cysteine substitutions in EGF-like domains represent the most common class of mutations causing Marfan syndrome, no mutation causing Marfan syndrome had been found in the specific domain harboring C1223Y. The demonstration that fibrillin-1 is expressed as early as the 8-cell stage of human development was considered consistent with a possible role for fibrillin-1 in early craniofacial and CNS development. See Sood et al. (1996) for further details. Also see 134797.0045 for another patient with features of both disorders.


.0023   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

FBN1, ARG2726TRP
SNP: rs61746008, gnomAD: rs61746008, ClinVar: RCV000029787, RCV000181628, RCV000243696, RCV000279856, RCV000306003, RCV000337198, RCV000394448, RCV000399653, RCV000586191, RCV001081571

This variant, formerly titled MARFANOID SKELETAL SYNDROME, has been reclassified based on the findings of Buoni et al. (2004) and Van Dijk et al. (2009).

Milewicz et al. (1995) demonstrated a profibrillin processing mutation in a 13-year-old boy with isolated skeletal features of the Marfan syndrome. He was 6 feet tall (more than 95th percentile for age) with upper-to-lower segment ratio of 0.89 and with pectus carinatum, scoliosis, arachnodactyly, and pes planus. Echocardiogram and eye examination were normal. Only one-half of the secreted profibrillin was proteolytically processed to fibrillin outside the cell and deposited in the extracellular matrix. Electron microscopic examination showed that rotary shadowed microfibrils made by the proband's fibroblasts were indistinguishable from control cells. Sequencing of the FBN1 gene demonstrated a heterozygous C-to-T transition at nucleotide 8176, resulting in the substitution of tryptophan for arginine (R2726W) at a site immediately adjacent to a consensus sequence recognized by a cellular protease. Six other individuals in the proband's family had the FBN1 mutation that segregated with tall stature. None of the affected individuals had cardiac or ocular manifestations of the Marfan syndrome. This mutation identified a putative site for profibrillin-to-fibrillin processing and was associated with isolated skeletal features of the Marfan syndrome, indicating to the authors that the FBN1 gene is one of the genes that determine height in the general population. The authors stated that the cellular effect of the mutation may be equivalent to a 'null' FBN1 mutation and is consistent with the mild phenotype associated with null alleles as opposed to the dominant-negative effect with severe phenotype observed with missense mutations.

Buoni et al. (2004) described the same R2726W mutation of FBN1 in an 18-year-old man and his 41-year-old mother. Both were of average height. The son had scoliosis, pectus carinatum, pes planus, arachnodactyly, and normal upper/lower segment ratio and arm span to height.

Van Dijk et al. (2009) reported the R2726W mutation in exon 64 of the FBN1 gene in phenotypically normal father and son. The mother and a second son had classic features of Marfan syndrome; she was heterozygous for a cysteine substitution in FBN1 (C1928S) and the son was compound heterozygous for the C1928S and the R2726W mutations. Van Dijk et al. (2009) stated that the son was more severely affected than his mother; he underwent aortic root surgery at a younger age (19 years with a measurement of 48 mm vs 35 years with a measurement of 60 mm), was treated for a type B aortic dissection at age 21 years, and had more skeletal features of MFS than his mother. This mutation may be associated with incomplete penetrance and may have no effect or only mild skeletal manifestations.


.0024   REMOVED FROM DATABASE


.0025   MARFAN SYNDROME

FBN1, CYS1117TYR
SNP: rs137854470, ClinVar: RCV000017890, RCV003764581

In a patient with Marfan syndrome (MFS; 154700), Tynan et al. (1993) identified a G-to-A change at nucleotide 3350 of the FBN1 gene, resulting in a cys1117-to-tyr substitution.


.0026   MARFAN SYNDROME

FBN1, CYS1242TYR
SNP: rs137854471, ClinVar: RCV000017891, RCV000812017

In a patient with Marfan syndrome (MFS; 154700), Kainulainen et al. (1994) identified a G-to-A change at nucleotide 3725 of the FBN1 gene, resulting in a cys1242-to-tyr substitution.


.0027   MARFAN SYNDROME, NEONATAL

FBN1, LYS1043ARG
SNP: rs137854472, gnomAD: rs137854472, ClinVar: RCV000017909, RCV002321486, RCV003764584

Wang et al. (1997) described 3 FBN1 mutations. Two of them were in patients with the neonatal form of Marfan syndrome (MFS; 154700); the third was in a patient with classic Marfan syndrome. All 3 occurred in the same region that had been found to harbor neonatal Marfan syndrome mutations. The first patient had striking skeletal features of Marfan syndrome, including soft, loose skin, crumpled ears, and joint contractures at birth. Eye and cardiac examinations were normal. At 7 months of age, he developed an aggressive scoliosis; however, his contractures were no longer evident. Hypotonia and marked mitral valve prolapse (which had not been evident at birth) were noted. At 14 months of age, an extensive mitral valve repair was performed. Postoperative complications necessitated replacement with a St. Jude mechanical prosthesis 3 weeks later and a porcine heterograft 2 months after the initial valve repair. At 20 months of age, he underwent plication of the right hemidiaphragm and resection of the bulbous cysts of the left lung. The patient died suddenly at 2 years of age. Diffuse changes of the Marfan syndrome were found in the vessels and emphysematous changes in the lungs at autopsy were noted. Amplified genomic DNA from the patient using intron primers to exon 25 showed heteroduplex formation when run on mutation detection enhancement (MDE) gels. Sequence analysis showed an A-to-G transition at position 3128 that caused a lysine-to-arginine substitution at amino acid position 1043 (K1043R) in 1 allele.


.0028   MARFAN SYNDROME, NEONATAL

FBN1, ASN1131TYR
SNP: rs137854473, ClinVar: RCV000017910

In a patient with the neonatal form of Marfan syndrome (MFS; 154700), Wang et al. (1997) described an A-to-T transversion at position 3391 in the FBN1 gene that caused an asparagine-to-tyrosine substitution at amino acid position 1131 (N1131Y).


.0029   MARFAN SYNDROME

FBN1, 1-BP DEL, 3192A
SNP: rs1131692050, ClinVar: RCV000017911

In a patient considered to have classic Marfan syndrome (MFS; 154700), Wang et al. (1997) used amplified genomic DNA and intron primers to exon 25 to demonstrate heteroduplex formation on mutation detection enhancement (MDE) gels. Sequence analysis showed a 1-bp deletion (A) at position 3192 in exon 25. This caused a frameshift and premature stop that would predict synthesis of a truncated protein of 1,086 amino acids. The change was not observed in either clinically unaffected parents and thus represented a de novo mutation. The patient was born with pectus excavatum that was repaired at age 13 years of age. He had mild scoliosis that required no treatment. When he was 20 years old, the question of Marfan syndrome was raised on the basis of his marfanoid habitus with upper-to-lower segment ratio of 0.88, high-arched palate, arachnodactyly, positive thumb and wrist signs, and mild hyperextensibility. Ophthalmologic examination was normal. Echocardiography showed mild aortic root dilation without valvular insufficiency. There was no evidence of mitral valve prolapse. He was treated with a beta-blocker. Echocardiogram 3 years later showed mild aortic insufficiency, normal left ventricular function, and aortic root diameter 4.2 cm, and again no mitral involvement. Wang et al. (1997) marveled at the fact that the mutation in this relatively mild, although classic, case of Marfan syndrome occurred in the same region as the mutations in 2 cases of neonatal Marfan syndrome (134797.0027, 134797.0028).


.0030   MARFAN SYNDROME

FBN1, 6354C-T, EX51DEL, ILE2118ILE
SNP: rs112989722, gnomAD: rs112989722, ClinVar: RCV000017912, RCV000483725, RCV000589136, RCV000704427, RCV002310629

Liu et al. (1997) carried out a systematic mutation search of PCR-amplified transcripts of the FBN1 gene from patients with Marfan syndrome (MFS; 154700). By long RT-PCR and restriction enzyme digestions, they identified skipping of FBN1 exons in 10% of Marfan cases. All but 1 of these were due to sequence alterations at splice sites. In skin fibroblasts derived from a patient with classic Marfan syndrome, an abnormally migrating restriction fragment was identified and found to represent deletion of 66 bp due to in-frame skipping of the entire exon 51. This exon encodes the 3-prime portion of 1 of the 7 8-cysteine domains in FBN1 that is similar to a motif found in transforming growth factor-beta-1 binding protein (150390). Sequencing of exon 51 and surrounding splice sites, amplified from genomic DNA with intron primers, identified only 1 sequence variation unique to this sample: a C-to-T transition (6354C-T) at position +41 of exon 51. This mutation changes codon 2118 from AUC to AUU, both of which encode isoleucine. Liu et al. (1997) stated that this nucleotide change is unlikely to affect known binding sites of the splicing machinery. Further studies indicated that the skipping of exon 51 in these cells was due solely to the silent mutation, 6354C-T. Skipping of exon 51 associated with a 6339T-G mutation that changes a tyrosine (TAT) to a termination (TAG) codon (134797.0008) was previously reported as the cause of exon 51 skipping (Dietz et al., 1993; Dietz and Kendzior, 1994). Liu et al. (1997) commented that skipping caused by a silent mutation suggests the existence of an alternative mechanism of exon skipping yet to be discovered.


.0031   MARFAN SYNDROME, CLASSIC

FBN1, CYS1265ARG
SNP: rs137854474, ClinVar: RCV000017913

Montgomery et al. (1998) found a T-to-C transition at nucleotide 3793 of the FBN1 gene, predicting the substitution of arginine for cysteine at codon 1265, within a calcium-binding epidermal growth factor-like domain of fibrillin-1 in a mother and son who fulfilled criteria for Marfan syndrome (MFS; 154700); 2 other sons of the woman seemed to have the Marfan syndrome, although in milder form. Haplotype analysis using 4 intragenic microsatellite polymorphic markers showed, however, that these 2 children could have not inherited the Marfan mutation, and indeed the mutation was not demonstrated in these children.


.0032   MASS SYNDROME

FBN1, ARG1170HIS
SNP: rs137854475, gnomAD: rs137854475, ClinVar: RCV000148494, RCV000154459, RCV000242225, RCV000290413, RCV000297783, RCV000305937, RCV000340663, RCV000357267, RCV000360569, RCV000589339, RCV000767968, RCV000845006, RCV001084627, RCV001837435, RCV003924840

Montgomery et al. (1998) described a G-to-A transition at nucleotide 3509 of the FBN1 coding sequence, predicted to result in the substitution of histidine for arginine at codon 1171, within a calcium-binding EGF-like domain of the protein. The clinical manifestations in several members of the family were suggestive of Marfan syndrome (154700) but did not satisfy the revised diagnostic criteria presented by De Paepe et al. (1996). Thus the disorder in this family was considered to be a subdiagnostic variant of Marfan syndrome; see MASS syndrome (604308). The proband, 46 years of age at the time of report, was diagnosed with a nonspecific connective tissue disorder because dolichostenomelia, joint hypermobility, kyphoscoliosis, pes planus, positive wrist and thumb signs, striae distensae, early myopia, and myxomatous mitral leaflets with mitral valve prolapse were found. There was no lens dislocation, and all aortic measurements were within normal limits when standardized to age and body surface area. Multiple family members, including all 4 of the proband's children and her brother, father, and paternal uncle, had a tall, thin body habitus and/or preadolescent myopia. Two individuals, the proband's father and eldest son, also showed more specific findings, including arachnodactyly, dolichostenomelia, pectus deformity, scoliosis, positive wrist and thumb signs, and mitral valve prolapse. Like the proband, neither of these individuals had lens dislocation or aortic dilatation.


.0033   MARFAN SYNDROME

FBN1, ARG529TER
SNP: rs137854476, ClinVar: RCV000017915, RCV000181685, RCV000586473, RCV000632013, RCV000769652, RCV000999929

In a patient with Marfan syndrome (MFS; 154700), Montgomery et al. (1998) found a C-to-T transition at nucleotide 1585 of the fibrillin-1 coding sequence, predicting substitution of a premature termination codon for arginine at codon 529, within a calcium-binding EGF-like domain of fibrillin-1. The diagnosis of Marfan syndrome was made in the patient at the age of 24 years when an echocardiogram showed dilatation of the aortic root to 8 cm and chronic dissection of the ascending aorta. Associated features included preadolescent myopia, dolichostenomelia, asymmetric pectus carinatum, scoliosis, joint hypermobility, pes planus, and widespread striae distensae. There was no lens dislocation. The proband's mother, 60 years of age at the time of report, showed only joint hypermobility, pes planus, and striae distensae of the abdomen and trunk. There was no myopia or lens dislocation, and all aortic measurements were within normal limits when standardized to age and body surface area. The mother was found to be mosaic for the arg529-to-ter mutation. The mutation was thought to be present in approximately 43% of lymphoblasts and in 51% of fibroblasts.


.0034   MARFAN SYNDROME, ATYPICAL

FBN1, GLY985GLU
SNP: rs137854477, ClinVar: RCV000017916, RCV002433459

In a family with an atypical form of Marfan syndrome (MFS; 154700), Collod-Beroud et al. (1999) demonstrated germline mosaicism for a gly985-to-glu (G985E) mutation of the FBN1 gene. The proband was a 16-year-old boy with dilation of the ascending aorta (46 mm at the sinuses of Valsalva, 8 SD above the mean when standardized to age and body surface area), mitral valve prolapse with regurgitation, highly arched palate, arachnodactyly (positive wrist and thumb signs), tall stature (199 cm, +4 SD, 76 kg), and scoliosis. His 9-year-old brother displayed dilation of the ascending aorta (32 mm at the sinuses of Valsalva, 6 SD above the mean when standardized to age and body surface area), arachnodactyly (positive wrist and thumb signs), dolichostenomelia (arm span-to-height ratio, 1.05), tall stature (144 cm, +3 SD, 31 kg), highly arched palate, and joint hypermobility. No other anomalies typical of MFS (including ectopia lentis) were found in either subject. Both parents had no sign suggesting MFS, and another brother was unaffected. The G985E substitution was present in heterozygous state and resulted from a G-to-A transition at nucleotide 2954. Several lines of evidence indicated that this was the disease-causing mutation: the mutation was not observed during screening of 306 chromosomes; the mutation substitutes an uncharged or negatively charged amino acid much higher in molecular weight; and the mutational event occurred in the 8-cysteine module 3 at a position conserved in bovine, murine, and porcine sequences. The G985E mutation created a new TaqI restriction site, resulting in 2 fragments of 202 and 217 bp by which the mutation could be sought in members of the family. The 217-bp fragment resulting from digestion was found at a very low level in the father's white blood cell DNA, but was not found in that from the mother or in controls. Careful reassessment of the clinical examination of the father (performed systematically before the identification of the mosaicism) revealed no skeletal or ocular sign but minor findings: discrete dilation of the ascending aorta (43 mm, +2 SD when standardized to age and body surface area (193 cm, 75 kg, at age 41 years)) and minimal aortic regurgitation. Collod-Beroud et al. (1999) commented that the G985E mutation, which occurred in exon 24, was not associated with ocular anomalies. This was of interest because study of the Marfan database (Collod-Beroud et al., 1998) indicated that half (9 of 19) of the mutations not associated with ocular anomaly were located in exons 23 to 29. This contrasted with mutations associated with a complete classic MFS phenotype, which were widely distributed throughout the gene.


.0035   MARFAN SYNDROME

FBN1, IVS2DS, G-A, +1
SNP: rs25404, ClinVar: RCV000035141, RCV000181642, RCV000526514, RCV000770680

In a Japanese patient with Marfan Syndrome, Chikumi et al. (2000) identified a recurrent de novo mutation, IVS2DS+1G-A. This mutation had been identified in a sporadic case by Dietz et al. (1993), who found that it resulted in a skipping of exon 2.


.0036   MARFAN SYNDROME

FBN1, GLY1013ARG
SNP: rs140593, ClinVar: RCV000017918

In 2 unrelated patients with atypically severe, early-onset manifestations of Marfan syndrome (MFS; 154700), Tiecke et al. (2001) identified a G-to-A transition at nucleotide 3037 in exon 24 of the FBN1 gene, resulting in a gly1013-to-arg (G1013R) substitution. In both cases the mutation was ruled out in the clinically unaffected parents. The G1013R mutation affects a highly conserved residue in the interdomain linkage region, which may play a role in interdomain flexibility. The mutation was first reported by Nijbroek et al. (1995) in a patient with atypically severe manifestations and it therefore represents a recurrent mutation. Tiecke et al. (2001) identified the G1013R mutation by heteroduplex screening in a fourth unrelated patient with severe clinical involvement, who was not a member of their initial screening group.


.0037   MARFAN SYNDROME

FBN1, 33-BP INS, IVS46, G-A, +1
SNP: rs1555395819, ClinVar: RCV000017919

Hutchinson et al. (2001) studied a patient with Marfan syndrome (MFS; 154700) whose mutation was not detected by heteroduplex analysis. Primary cultured patient fibroblasts were metabolically labeled and found to secrete fibrillin-1 defectively when compared with an age-matched control. Sequencing of patient cDNA, isolated by RT-PCR of patient fibroblast RNA, detected a 33-bp insertion. The reading frame of the mutant allele was maintained and predicted the insertion of 11 amino acids at the beginning of calcium-binding epidermal growth factor-like domain 29. Direct sequencing of genomic DNA detected a heterozygous G-to-A transversion at the +1 position of intron 46 of the FBN1 gene. The 11-amino acid insertion was a consequence of the usage of a cryptic splice site 33 bp downstream of the mutation. This was the first reported case of a splicing defect in FBN1 leading to the production of a full length fibrillin-1 transcript containing a large amino acid insertion. The patient represented a sporadic case of Marfan syndrome. At the age of 27 years he showed skeletal features including pectus excavatum, an arm span-to-height ratio of 1.09, arachnodactyly, kyphoscoliosis, highly arched palate with dental crowding, and typical facial appearance (downslanting palpebral fissures, enophthalmos, and malar hypoplasia). He had bilateral ectopia lentis and underwent aortic root replacement at the age of 23 years.


.0038   MARFAN SYNDROME, NEONATAL

FBN1, GLU1073LYS
SNP: rs137854478, ClinVar: RCV000017920, RCV000181482, RCV000227621, RCV000582993, RCV000684781, RCV002313714

The glu1073-to-lys (E1073K) mutation in FBN1, found in a patient with Marfan syndrome of the severe neonatal form (MFS; 154700), was used by Reinhardt et al. (2000) to demonstrate that mutations in calcium-binding epidermal growth factor modules render fibrillin-1 susceptible to proteolysis.

The same mutation was found by Ades et al. (2006) in a patient with arachnodactyly noted at birth and with ophthalmologic findings at age 5 months that included bilateral lens dislocation.


.0039   MARFAN SYNDROME

FBN1, IVS46+5G-A
SNP: rs193922219, gnomAD: rs193922219, ClinVar: RCV000035236, RCV000181550, RCV000415118, RCV000684778, RCV000781375, RCV001170536, RCV002287351, RCV003914915

In patients with Marfan syndrome (MFS; 154700), Nijbroek et al. (1995) and Liu et al. (1996) reported skipping of exon 46 of the FBN1 gene due to a G-to-A transition at the +5 position of the consensus 5-prime splice site. Collod-Beroud et al. (2003) noted that this mutation was the most frequently recurring mutation to that time, having been reported a total of 9 times.


.0040   WEILL-MARCHESANI SYNDROME 2

FBN1, 24-BP DEL
SNP: rs1555396783, ClinVar: RCV000017922

In affected members of a family with autosomal dominant Weill-Marchesani syndrome (WMS2; 608328) first reported by Gorlin et al. (1974), Faivre et al. (2003) identified heterozygosity for a 24-bp in-frame deletion (5074del24) in exon 41 of the FBN1 gene. The mutation cosegregated with disease and was not found in 186 controls.


.0041   MARFAN SYNDROME

FBN1, TYR754CYS
SNP: rs137854479, ClinVar: RCV000017923, RCV000587806, RCV003764585

In a family of Australian Aboriginal/European background extensively affected with Marfan syndrome (MFS; 154700), Summers et al. (2004) identified a 2262A-G transition in the FBN1 gene, resulting in a tyr754-to-cys (Y754C) mutation. The addition or removal of cysteine in the calcium-binding EGF domains of fibrillin had consistently been associated with Marfan syndrome, supporting the pathogenic nature of the mutation. Furthermore, the mutation affects a conserved tyrosine that is involved in the interaction between adjacent EGF domains.


.0042   MARFAN SYNDROME

ECTOPIA LENTIS 1, ISOLATED, AUTOSOMAL DOMINANT, INCLUDED
FBN1, ARG240CYS
SNP: rs137854480, ClinVar: RCV000017924, RCV000017925, RCV000181681, RCV000515367, RCV000631968, RCV001170326, RCV002307365

Edwards et al. (1994) described a large kindred with ectopia lentis (ECTOL1; 129600) showing linkage to FBN1. Ades et al. (2004) provided follow-up data on the family and demonstrated an arg240-to-cys (R240C) mutation in the FBN1 gene. The same mutation had been reported 3 times previously: once in a family with classic Marfan syndrome (MFS; 154700), including a 31-year-old patient with major skeletal, ocular, and cardiovascular manifestations (Loeys et al., 2001); once in 1 member of a multigenerational ectopia lentis kindred (Korkko et al., 2002); and once in an adult from a familial ectopia lentis kindred who had ectopia lentis and involvement of the integument, without cardiovascular involvement (Comeglio et al., 2002).

Faivre et al. (2007) found that a missense mutation substituting or producing cysteine was associated with a high probability of ectopia lentis when compared with other missense mutations.


.0043   MARFAN SYNDROME, NEONATAL

FBN1, CYS1032TYR
SNP: rs137854481, ClinVar: RCV000017926, RCV000532010

In a male infant with the neonatal form of Marfan syndrome (MFS; 154700) leading to death at the age of 4 months, Elcioglu et al. (2004) identified a heterozygous 3095G-A transition in exon 25 of the FBN1 gene, resulting in a cys1032-to-tyr (C1032Y) substitution. The infant had severe arachnodactyly, hypermobility of the fingers, flexion contractures of elbows, wrists, hips, and knees, microretrognathia, crumpled ears, 'rocker-bottom' feet, loose redundant skin, and lens dislocations. The cause of death was cardiac failure from cardiac valve insufficiency and aortic dilatation.


.0044   MARFAN SYNDROME

FBN1, CYS1129TYR
SNP: rs137854482, ClinVar: RCV000017927, RCV002514108

In a sporadic case of Marfan syndrome, El-Aleem et al. (1999) identified a 3386G-A transition in the FBN1 gene, resulting in a cys1129-to-tyr (C1129Y) substitution.


.0045   MARFAN SYNDROME

FBN1, CYS1221TYR
SNP: rs137854483, ClinVar: RCV000030943

In a Japanese boy with Marfan syndrome (MFS; 154700) who also had features of Shprintzen-Goldberg syndrome (182212), including craniosynostosis and mental retardation, Kosaki et al. (2006) identified heterozygosity for a 3662G-A transition in the FBN1 gene, resulting in a cys1221-to-tyr (C1221Y) substitution in an EGF-like domain. The boy had pectus carinatum, scoliosis, arachnodactyly with contractures of the interphalangeal joints, pes planus, and dolichocephaly. An echocardiogram demonstrated minimal enlargement of the aortic root and mitral valve prolapse with mild tricuspid insufficiency. Also see 134797.0022 for another patient with features of both disorders.


.0046   MARFAN SYNDROME, NEONATAL

FBN1, CYS1086TYR
SNP: rs137854484, ClinVar: RCV000017929

In a male infant with severe neonatal Marfan syndrome (MFS; 154700), Tekin et al. (2007) identified a heterozygous 3257G-A transition in exon 25 of the FBN1 gene, resulting in a cys1086-to-tyr (C1086Y) substitution in the EGF-like domain. Two older brothers were similarly affected, and all 3 sibs died at ages 2 to 4 months of cardiorespiratory insufficiency. Mosaicism for the mutation was identified in somatic cells and germ cells of the clinically unaffected father. Tekin et al. (2007) stated that this was the first report of familial neonatal Marfan syndrome.


.0047   MARFAN SYNDROME, AUTOSOMAL RECESSIVE

FBN1, ARG485CYS
SNP: rs137854485, ClinVar: RCV000017930, RCV000150705, RCV000663457, RCV000809693, RCV002390114

In 2 cousins with Marfan syndrome (MFS; 154700) in a consanguineous Turkish family, de Vries et al. (2007) identified homozygosity for a 1453C-T transition in exon 11 of the FBN1 gene, resulting in an arg485-to-cys (R485C) substitution. All 4 healthy parents were heterozygous for the mutation and none fulfilled the Ghent criteria for Marfan syndrome. The mutation is located in a calcium-binding EGF-like domain and was not found in 500 control chromosomes.


.0048   MARFAN SYNDROME

FBN1, 302.5-KB DEL
ClinVar: RCV000017931

In a patient with Marfan syndrome (MFS; 154700) in whom no mutation was detected by standard genetic testing, Matyas et al. (2007) used multiplex ligation-dependent probe analysis (MLPA) and high-density SNP arrays to analyze the FBN1 gene and identified a 302,580-bp deletion, involving the putative regulatory and promoter regions of FBN1 as well as a neighboring gene, CEP152 (613529). Sequence analysis of RT-PCR products revealed transcripts from only 1 allele, indicating true haploinsufficiency.


.0049   MARFAN SYNDROME

FBN1, EX13-49DEL
ClinVar: RCV000017932

In a girl with severe early-onset Marfan syndrome (MFS; 154700), Blyth et al. (2008) identified somatic mosaicism for a heterozygous deletion of exons 13 through 49 of the FBN1 gene in both peripheral blood and saliva. She was diagnosed at age 3 years due to subluxation of the lenses, marked myopia, ligamentous laxity and valgus ankles. Echocardiogram at age 3 showed dilation of the aortic root to the upper limits of normal and mild tricuspid regurgitation. Other features apparent by age 4 included joint hypermobility, scoliosis, arachnodactyly, high-arched palate, and thin, long face. Blyth et al. (2008) suggested that Marfan patients with FBN1 deletions have a more severe phenotype.


.0050   STIFF SKIN SYNDROME

FBN1, TRP1570CYS, 4710G-T
SNP: rs267606799, ClinVar: RCV000017933

In affected members of a 5-generation family segregating autosomal dominant stiff skin syndrome (184900), Loeys et al. (2010) identified heterozygosity for a 4710G-T transversion in exon 37 of the FBN1 gene, resulting in a trp1570-to-cys (W1570C) substitution at a key structural residue in the N-terminal portion of the fourth TGF-beta (190180)-binding protein-like domain (N-TB4). The mutation was not found in more than 400 ethnically matched control chromosomes.

In transiently transfected HEK293 cells and in the MSU-1.1 human fibroblast cell line, Jensen et al. (2015) demonstrated that the W1570C mutant is secreted into the extracellular media and incorporates into the microfibril network.


.0051   STIFF SKIN SYNDROME

FBN1, TRP1570CYS, 4710G-C
SNP: rs267606799, ClinVar: RCV000017934

In 3 affected members of a family segregating autosomal dominant stiff skin syndrome (184900), Loeys et al. (2010) identified heterozygosity for a 4710G-C transversion in exon 37 of the FBN1 gene, resulting in a trp1570-to-cys (W1570C) substitution at a key structural residue in the N-terminal portion of the TB4 domain. The mutation was not found in more than 400 ethnically matched control chromosomes.

In transiently transfected HEK293 cells and in the MSU-1.1 human fibroblast cell line, Jensen et al. (2015) demonstrated that the W1570C mutant is secreted into the extracellular media and incorporates into the microfibril network.


.0052   STIFF SKIN SYNDROME

FBN1, CYS1564SER
SNP: rs267606800, ClinVar: RCV000017935

In 3 affected members of a family segregating autosomal dominant stiff skin syndrome (184900), Loeys et al. (2010) identified heterozygosity for a 4691G-C transversion in exon 37 of the FBN1 gene, resulting in a cys1564-to-ser (C1564S) substitution at an evolutionarily conserved residue in the N-terminal portion of the TB4 domain. The mutation was not found in more than 400 ethnically matched control chromosomes.

In transiently transfected HEK293 cells and in the MSU-1.1 human fibroblast cell line, Jensen et al. (2015) demonstrated that the C1564S mutant is secreted into the extracellular media and incorporates into the microfibril network.


.0053   STIFF SKIN SYNDROME

FBN1, CYS1577GLY
SNP: rs267606801, ClinVar: RCV000017936

In a 54-year-old man with stiff skin syndrome (184900), Loeys et al. (2010) identified heterozygosity for a 4729T-G transversion in exon 37 of the FBN1 gene, resulting in a cys1577-to-gly (C1577G) substitution at an evolutionarily conserved residue in the N-terminal portion of the TB4 domain. The mutation was not found in more than 400 ethnically matched control chromosomes.


.0054   STIFF SKIN SYNDROME

FBN1, GLY1594ASP
SNP: rs267606798, ClinVar: RCV000017937, RCV000035211, RCV003298043

In a 14-year-old boy with stiff skin syndrome (184900) associated with ectopia lentis, Loeys et al. (2010) identified heterozygosity for a de novo 4781G-A transition in exon 38 of the FBN1 gene, resulting in a gly1594-to-asn (G1594N) substitution in the C-terminal portion of the TB4 domain (C-TB4). The mutation was not found in more than 400 ethnically matched control chromosomes. This mutation was erroneously published as GLY1594ASN; Dietz (2014) confirmed that the correct substitution is GLY1594ASP.


.0055   GELEOPHYSIC DYSPLASIA 2

ACROMICRIC DYSPLASIA, INCLUDED
FBN1, TYR1699CYS
SNP: rs387906622, ClinVar: RCV000022543, RCV000022544, RCV002513168

In 5 patients with geleophysic dysplasia-2 (GPHYSD2; 614185) and 1 with acromicric dysplasia (ACMICD; 102370), Le Goff et al. (2011) identified heterozygosity for a 5096A-G transition in the FBN1 gene, resulting in a tyr1699-to-cys (Y1699C) substitution within the TGFB (190180)-binding protein-like 5 (TB5) domain. The mutation was not found in 2,000 ethnically matched controls or in the Marfan mutation database.


.0056   GELEOPHYSIC DYSPLASIA 2

FBN1, GLY1762SER
SNP: rs387906623, gnomAD: rs387906623, ClinVar: RCV000022545, RCV000255619, RCV000624204, RCV001389174

In 6 patients with geleophysic dysplasia-2 (GPHYSD2; 614185), Le Goff et al. (2011) identified heterozygosity for a 5284G-A transition in the FBN1 gene, resulting in a gly1762-to-ser (G1762S) substitution within the TB5 domain. The mutation was not found in 2,000 ethnically matched controls or in the Marfan mutation database.

In transiently transfected HEK293 cells and in the MSU-1.1 human fibroblast cell line, Jensen et al. (2015) demonstrated that the G1762S mutant is secreted into the extracellular media and incorporates into the microfibril network.


.0057   GELEOPHYSIC DYSPLASIA 2

ACROMICRIC DYSPLASIA, INCLUDED
FBN1, ALA1728THR
SNP: rs387906624, ClinVar: RCV000022546, RCV000022547

In 1 patient with geleophysic dysplasia-2 (GPHYSD2; 614185) and 1 with acromicric dysplasia (ACMICD; 102370), Le Goff et al. (2011) identified heterozygosity for a 5182G-A transition in the FBN1 gene, resulting in an ala1728-to-thr (A1728T) substitution within the TB5 domain. The mutation, which was de novo in both patients, was not found in 2,000 ethnically matched controls or in the Marfan mutation database.


.0058   GELEOPHYSIC DYSPLASIA 2

FBN1, TYR1696CYS
SNP: rs387906625, ClinVar: RCV000022548, RCV001262145, RCV003764623

In 2 unrelated patients with geleophysic dysplasia-2 (GPHYSD2; 614185), both of whom died in the first decade of life, Le Goff et al. (2011) identified heterozygosity for a 5087A-G transition in the FBN1 gene, resulting in a tyr1696-to-cys (Y1696C) substitution within the TB5 domain. One patient was Belgian and had mitral stenosis and insufficiency, underwent tracheotomy at age 3 years, and died at 9 years of age. The other patient, who was from the U.K. and had respiratory insufficiency, pulmonary artery hypertension, and sleep apnea, died at 3 years of age. The mutation, which was de novo in both patients, was not found in 2,000 ethnically matched controls or in the Marfan mutation database.


.0059   ACROMICRIC DYSPLASIA

FBN1, SER1750ARG
SNP: rs1131692052, ClinVar: RCV000022549, RCV001596938

In a French mother and 2 children with acromicric dysplasia (ACMICD; 102370), Le Goff et al. (2011) identified heterozygosity for a 5251T-G transversion in the FBN1 gene, resulting in a ser1750-to-arg (S1750R) substitution within the TB5 domain. The mutation was not found in 2,000 ethnically matched controls or in the Marfan mutation database.


.0060   ACROMICRIC DYSPLASIA

FBN1, TYR1700CYS
SNP: rs387906626, ClinVar: RCV000022550, RCV000494669, RCV001851997

In a Chinese mother and child with acromicric dysplasia (ACMICD; 102370), Le Goff et al. (2011) identified heterozygosity for a 5099A-G transition in the FBN1 gene, resulting in a tyr1700-to-cys (Y1700C) substitution within the TB5 domain. The mutation was not found in 2,000 ethnically matched controls or in the Marfan mutation database.

In transiently transfected HEK293 cells and in the MSU-1.1 human fibroblast cell line, Jensen et al. (2015) demonstrated that the Y1700C mutant is secreted into the extracellular media and incorporates into the microfibril network.


.0061   ACROMICRIC DYSPLASIA

FBN1, 3-BP DUP, NT5202
SNP: rs587776863, ClinVar: RCV000022551

In a French patient with acromicric dysplasia (ACMICD; 102370), Le Goff et al. (2011) identified heterozygosity for a 3-bp duplication at nucleotide 5202 in the FBN1 gene, resulting in duplication of a glutamine at codon 1735 (gln1735dup) within the TB5 domain. The mutation was not found in 2,000 ethnically matched controls or in the Marfan mutation database.


.0062   FNB1 POLYMORPHISM

FBN1, PRO1148ALA
SNP: rs140598, gnomAD: rs140598, ClinVar: RCV000029726, RCV000030812, RCV000035172, RCV000461828, RCV000770675, RCV001118162, RCV001119710, RCV001119711, RCV001119712, RCV001119713, RCV001811206, RCV002276585

Dietz et al. (1995) reported an 11-year-old girl with typical features of Marfan syndrome who also had hypotonia, scaphocephaly with craniosynostosis, ocular proptosis, low-set anomalous ears, micrognathia, hyperelastic skin, umbilical hernia, talipes equinovarus, and mental retardation. In this patient, Dietz et al. (1995) identified a C-to-G transversion at nucleotide 3442, substituting alanine for proline at codon 1148 (P1148A) within an EGF-like domain. This mutation was not present in the mother; the father's DNA was not available for study. The same mutation had been found in apparently unaffected members of families with Marfan syndrome or an isolated aortic aneurysm and had been found with much higher frequency in families affected by Marfan syndrome than in controls (Tynan et al., 1993). Indeed, Dietz et al. (1995) had identified P1148A in approximately 5% of the affected families, but in none of over 300 chromosomes from a control population. This suggested that P1148A defines a predisposing allele that is subject to extreme modification by epistatic, stochastic, and/or environmental modifiers. Sood et al. (1996) reported further on these 2 patients. Schrijver et al. (1997) screened 416 unrelated control individuals for the P1148A substitution and found an allele frequency of 3.8%. They observed a similar allele frequency (3%) after screening 133 patients with connective tissue disorders, including 55 with Marfan syndrome and 54 with aortic aneurysms. The authors concluded that the P1148A substitution is a polymorphism of no clinical significance. Watanabe et al. (1997) came to similar conclusions. In 3 unrelated Japanese patients with Shprintzen-Goldberg syndrome, they found that 1 was heterozygous for P1148A, 1 was homozygous for this substitution, and the third was homozygous for the wildtype allele. Among 3 healthy relatives of the SGS patient who was homozygous for P1148A, 2 (the mother and maternal grandmother) were found to be homozygous and 1 (the brother) to be heterozygous. In 161 native Japanese persons without SGS or Marfan syndrome, they found that 11 were P1148A homozygotes and 49 were heterozygotes. The estimated allele frequency of P1148A was calculated to be 0.22 among native Japanese. Wang et al. (1997) identified 5 individuals with P1148A in a mixed patient population, but none in 120 Caucasian or 50 African American controls. They found that 3 of the 5 individuals were Japanese. They also found that 8 of 25 native Chinese individuals were heterozygous and none homozygous for P1148A. Thus, Watanabe et al. (1997) concluded that P1148A is a polymorphic variant with increased frequency in Asian populations.


.0063   MARFAN SYNDROME

ECTOPIA LENTIS 1, ISOLATED, AUTOSOMAL DOMINANT, INCLUDED
FBN1, ARG974CYS
SNP: rs397514558, ClinVar: RCV000032871, RCV000172857, RCV000548224, RCV000726909, RCV001186221, RCV001192805

In a 55-year-old patient with Marfan syndrome (MFS; 154700), who had major skeletal, ocular, and cardiovascular manifestations as well as minor skin involvement, Comeglio et al. (2007) identified heterozygosity for a c.2920C-T transition in the FBN1 gene, resulting in an arg974-to-cys (R974C) substitution.

In 9 affected members of a 5-generation Chinese family with isolated ectopia lentis (ECTOL1; 129600), Yang et al. (2012) identified heterozygosity for the 2920C-T transition in exon 25 of the FBN1 gene, resulting in an R974C substitution at a highly conserved residue in the 8-cys repeat latent transforming growth factor-beta binding protein (LTBP) motif. The mutation was not found in 2 unaffected family members or in 50 ethnically matched controls.


.0064   MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME

FBN1, 2-BP DEL, 8155AA
SNP: rs398122831, ClinVar: RCV000033241

In a 27-year-old German woman with marfanoid-progeroid-lipodystrophy syndrome (MFLS; 616914), Graul-Neumann et al. (2010) identified heterozygosity for a de novo 2-bp deletion (8155_8156delAA) in exon 64 of the FBN1 gene, causing a frameshift that generates a premature stop codon 17 residues downstream (Lys2719AspfsTer18). The mutation was not present in either parent or in 150 unrelated controls. The patient fulfilled the clinical Ghent criteria for Marfan syndrome with 3 major features, including ectopia lentis, aortic dilatation, and dural ectasia, but also showed an extreme reduction in the amount of subcutaneous fat tissue since birth and had prominent facial lipodystrophy.


.0065   MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME

FBN1, 20-BP DEL, NT8156
SNP: rs398122832, ClinVar: RCV000033242

In a 20-year-old man of Irish ancestry with marfanoid-progeroid-lipodystrophy syndrome (MFLS; 616914), Goldblatt et al. (2011) identified heterozygosity for a de novo 20-bp deletion (8156_8175del) in exon 64 of the FBN1 gene, causing a frameshift resulting in a premature stop codon (Lys2719Thrfster12). The mutation was not found in his unaffected parents. The patient had marfanoid features, including arachnodactyly with generalized mild digital hyperextensibility and bilateral lens subluxations, as well as decreased subcutaneous fat of neonatal onset with a progeroid facial appearance.


.0066   MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME

FBN1, IVS64DS, G-T, +1
SNP: rs398122833, ClinVar: RCV000033243, RCV001386016

In a 3.5-year-old girl with marfanoid-progeroid-lipodystrophy syndrome (MFLS; 616914), Horn and Robinson (2011) identified heterozygosity for a de novo splice site transversion (8226+1G-T) in intron 64 of the FBN1 gene, predicted to cause use of a noncanonical splice site resulting in a frameshift of the sequence encoded by exon 65. The mutation was not found in her parents or in 150 controls. The girl had tall stature, arachnodactyly, decreased subcutaneous fat, and a progeroid facial appearance.

In a female patient with congenital partial lipodystrophy and a progeroid appearance, Romere et al. (2016) identified heterozygosity for the c.8226+1G-T mutation in the FBN1 gene, which occurred de novo. The authors noted that she also carried a heterozygous c.8222T-C missense variant in FBN1, which was predicted to be benign. No additional clinical information was provided for this patient. The patient's overnight-fasted plasma insulin level was 2-fold lower than that of controls, while maintaining euglycemia. In addition, measurement of the C-terminal cleavage product, which the authors designated 'asprosin,' showed greater reduction than would be expected from the heterozygous genotype, suggestive of a dominant-negative effect. Overexpression of the truncated mutant version of profibrillin in wildtype human dermal fibroblasts confirmed interference with the ability of those cells to secrete asprosin.


.0067   MARFAN SYNDROME

FBN1, 7-BP DEL, NT4253
SNP: rs398122934, ClinVar: RCV000034311

In a 16-year-old Hispanic boy with Marfan syndrome (MFS; 154700) who had moderate aortic root dilation, descending aortic dissection, mild pectus excavatum, striae atrophica, and myopia, Brautbar et al. (2010) identified heterozygosity for a 7-bp deletion (4253_4259delGCCAGTG) in exon 34 of the FBN1 gene, causing a frameshift predicted to result in a premature stop codon 55 codons downstream. The aortic dissection originated immediately distal to the origin of the left subclavian artery, extended into the abdominal aorta, and terminated at the level of the right common iliac artery. His father had died suddenly at 41 years of age from a brain aneurysm after a long history of diabetes and hypertension. Although the patient had no documentation of hypertension before his admission, the postoperative period was complicated by persistent hypertension with maximum systolic pressures of 145 mm Hg.


.0068   MARFAN SYNDROME, AUTOSOMAL RECESSIVE

FBN1, ARG2576CYS ({dbSNP rs147195031})
SNP: rs147195031, gnomAD: rs147195031, ClinVar: RCV000029780, RCV000083258, RCV000539171, RCV000788741, RCV001374808, RCV002399340, RCV003492302, RCV003914867

In a Mexican American woman with Marfan syndrome (MFS; 154700), born of a consanguineous union, Hogue et al. (2013) identified homozygosity for a C-to-T transition at nucleotide 7726 of the FBN1 gene, resulting in an arg-to-cys substitution at codon 2576 (R2576C). The severe phenotype included pectus carinatum, scoliosis, arachnodactyly, ectopia lentis, mitral valve prolapse, aortic dilation, dural ectasias, and anterior sacral meningocele. She had a narrow, asymmetric face, dolichocephaly, hypertelorism with an interpupillary distance of 6.4 cm, downslanting palpebral fissures, and kyphoscoliosis. She also had moderate hydrocephalus and mild cognitive impairment. At 18 years, her height was 155 cm (10th percentile), with a span-to-height ratio of 1.05. At 20 years of age she became pregnant. Her aortic root was 4.3 cm at 14 weeks' gestation. At 30 weeks she developed chest pain and dyspnea; CT scan showed new aortic insufficiency and dilation. Cesarean section and aortic root repair of a type A dissection were performed. Her son was small for gestational age but healthy. He had dolichocephaly, downslanting palpebral fissures, midface hypoplasia, high narrow palate, and mild right knee contracture. Ophthalmology exam and echocardiogram were normal. The proband's mother had no stigmata of Marfan syndrome; the proband's father had had a cardiac event attributed to drug abuse. He reportedly had no other features of Marfan syndrome, but was unavailable for examination. The R2576C mutation was not present in the Exome Variant Server or the database of FBN1 mutations, but was recorded as rs147195031 with an estimated heterozygosity score of 0 +/- 0.015. Hogue et al. (2013) concluded that presumably this is a hypomorphic allele of FBN1, not causing disease when present in heterozygosity but leading to severe disease in homozygosity.


.0069   MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME

FBN1, 8-BP DEL, NT8175
SNP: rs876657410, ClinVar: RCV000210932

In a 10-year-old Japanese girl with marfanoid-progeroid-lipodystrophy syndrome (MFLS; 616914), Takenouchi et al. (2013) identified heterozygosity for an 8-bp deletion (c.8175_8182del8) in exon 64 of the FBN1 gene, causing a frameshift predicted to result in premature termination (Arg2726GlufsTer9).


.0070   MARFANOID-PROGEROID-LIPODYSTROPHY SYNDROME

FBN1, IVS64DS, G-A, +1
SNP: rs398122833, ClinVar: RCV000210934, RCV000631959, RCV000664017, RCV001566353

In a 16-year-old girl with marfanoid-progeroid-lipodystrophy syndrome (MFLS; 616914), originally reported by Verloes et al. (1998), Jacquinet et al. (2014) identified heterozygosity for a de novo donor splice site mutation in intron 64 (c.8226+1G-A). Analysis of the PCR product from patient skin fibroblast culture showed that exon 64 was skipped, causing a frameshift at the beginning of exon 65 and resulting in a premature termination codon (His2685IlefsTer9).


See Also:

Menton and Hess (1980)

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Contributors:
Marla J. F. O'Neill - updated : 11/12/2020
Ada Hamosh - updated : 02/27/2019
Marla J. F. O'Neill - updated : 02/23/2018
Marla J. F. O'Neill - updated : 4/28/2016
Marla J. F. O'Neill - updated : 2/8/2016
Marla J. F. O'Neill - updated : 6/5/2015
Ada Hamosh - updated : 4/16/2015
Ada Hamosh - updated : 1/10/2014
Ada Hamosh - updated : 11/20/2013
Marla J. F. O'Neill - updated : 3/22/2013
Marla J. F. O'Neill - updated : 3/12/2013
Marla J. F. O'Neill - updated : 1/25/2013
Patricia A. Hartz - updated : 2/17/2012
Marla J. F. O'Neill - updated : 8/22/2011
Marla J. F. O'Neill - updated : 6/14/2011
Ada Hamosh - updated : 7/12/2010
Marla J. F. O'Neill - updated : 4/2/2010
Patricia A. Hartz - updated : 3/18/2010
Marla J. F. O'Neill - updated : 1/27/2010
Marla J. F. O'Neill - updated : 10/30/2009
Cassandra L. Kniffin - updated : 5/14/2009
Cassandra L. Kniffin - updated : 4/16/2009
Marla J. F. O'Neill - updated : 3/26/2009
Patricia A. Hartz - updated : 2/17/2009
Cassandra L. Kniffin - updated : 6/16/2008
Marla J. F. O'Neill - updated : 3/18/2008
Kelly A. Przylepa - updated : 10/1/2007
Victor A. McKusick - updated : 8/16/2007
Cassandra L. Kniffin - updated : 5/17/2007
Cassandra L. Kniffin - updated : 9/21/2006
Victor A. McKusick - updated : 6/5/2006
Marla J. F. O'Neill - updated : 1/25/2006
Victor A. McKusick - updated : 1/6/2006
Paul J. Converse - updated : 10/4/2005
George E. Tiller - updated : 9/9/2005
Joanna S. Amberger - updated : 6/17/2005
Marla J. F. O'Neill - updated : 3/29/2005
Victor A. McKusick - updated : 3/15/2005
George E. Tiller - updated : 2/17/2005
Marla J. F. O'Neill - updated : 1/28/2005
Victor A. McKusick - updated : 9/15/2004
Victor A. McKusick - updated : 9/2/2004
Victor A. McKusick - updated : 8/23/2004
Victor A. McKusick - updated : 4/14/2004
Victor A. McKusick - updated : 2/25/2004
Cassandra L. Kniffin - updated : 12/9/2003
Victor A. McKusick - updated : 10/14/2003
Victor A. McKusick - updated : 3/5/2003
Victor A. McKusick - updated : 2/28/2003
Victor A. McKusick - updated : 2/25/2003
Victor A. McKusick - updated : 11/5/2002
Victor A. McKusick - updated : 9/25/2002
Victor A. McKusick - updated : 9/24/2002
Victor A. McKusick - updated : 8/16/2002
Victor A. McKusick - updated : 4/12/2002
Victor A. McKusick - updated : 12/27/2001
Michael B. Petersen - updated : 7/16/2001
Victor A. McKusick - updated : 2/21/2001
George E. Tiller - updated : 10/26/2000
Victor A. McKusick - updated : 9/28/2000
Michael J. Wright - updated : 6/19/2000
Wilson H. Y. Lo - updated : 4/24/2000
Victor A. McKusick - updated : 3/24/2000
Victor A. McKusick - updated : 9/23/1999
Victor A. McKusick - updated : 12/18/1998
Victor A. McKusick - updated : 7/1/1998
Victor A. McKusick - updated : 1/12/1998
Victor A. McKusick - updated : 10/14/1997
Victor A. McKusick - updated : 10/13/1997
Victor A. McKusick - updated : 10/9/1997
Victor A. McKusick - updated : 7/31/1997
Ada Hamosh - updated : 7/10/1997
Victor A. McKusick - updated : 6/23/1997
Victor A. McKusick - updated : 4/24/1997
Victor A. McKusick - updated : 3/21/1997
Moyra Smith - updated : 1/29/1997
Moyra Smith - updated : 10/23/1996
Stylianos E. Antonarakis - updated : 7/15/1996
Harry C. Dietz - updated : 6/16/1995

Creation Date:
Victor A. McKusick : 5/7/1991

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alopez : 08/11/2023
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alopez : 07/19/2023
carol : 10/03/2022
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alopez : 11/12/2020
carol : 02/28/2019
alopez : 02/27/2019
carol : 02/23/2018
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carol : 2/8/2016
alopez : 6/8/2015
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alopez : 5/14/2014
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terry : 3/22/2013
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carol : 1/25/2013
alopez : 11/13/2012
terry : 10/5/2012
carol : 10/4/2012
carol : 10/3/2012
carol : 10/3/2012
alopez : 5/15/2012
terry : 4/9/2012
mgross : 2/17/2012
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carol : 7/12/2010
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mgross : 3/18/2010
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wwang : 1/28/2010
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joanna : 11/9/2009
carol : 11/5/2009
terry : 10/30/2009
wwang : 6/25/2009
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ckniffin : 5/14/2009
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ckniffin : 6/16/2008
wwang : 3/26/2008
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mgross : 10/4/2005
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terry : 9/9/2005
carol : 6/20/2005
joanna : 6/17/2005
carol : 6/9/2005
wwang : 4/1/2005
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terry : 3/29/2005
terry : 3/15/2005
carol : 3/4/2005
wwang : 2/22/2005
terry : 2/17/2005
terry : 2/3/2005
terry : 1/28/2005
carol : 11/4/2004
tkritzer : 9/20/2004
terry : 9/15/2004
alopez : 9/5/2004
terry : 9/2/2004
tkritzer : 9/1/2004
terry : 8/23/2004
alopez : 5/25/2004
terry : 4/14/2004
tkritzer : 2/26/2004
terry : 2/25/2004
carol : 12/12/2003
ckniffin : 12/9/2003
alopez : 10/14/2003
carol : 3/13/2003
terry : 3/12/2003
tkritzer : 3/11/2003
terry : 3/5/2003
alopez : 2/28/2003
alopez : 2/25/2003
carol : 11/12/2002
tkritzer : 11/11/2002
terry : 11/5/2002
carol : 10/4/2002
tkritzer : 9/25/2002
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cwells : 9/24/2002
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terry : 8/16/2002
ckniffin : 6/5/2002
cwells : 4/22/2002
terry : 4/12/2002
mgross : 4/8/2002
cwells : 1/14/2002
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terry : 12/27/2001
carol : 7/16/2001
cwells : 2/27/2001
terry : 2/21/2001
carol : 11/2/2000
mcapotos : 10/26/2000
mcapotos : 10/17/2000
mcapotos : 10/13/2000
terry : 9/28/2000
mcapotos : 9/7/2000
alopez : 6/19/2000
carol : 5/30/2000
terry : 4/24/2000
mcapotos : 4/18/2000
carol : 3/29/2000
terry : 3/24/2000
mgross : 11/22/1999
alopez : 11/16/1999
carol : 11/11/1999
mgross : 10/6/1999
terry : 9/23/1999
kayiaros : 7/12/1999
carol : 5/20/1999
carol : 12/29/1998
carol : 12/29/1998
terry : 12/23/1998
terry : 12/18/1998
dkim : 12/11/1998
dkim : 12/10/1998
dkim : 9/11/1998
carol : 7/14/1998
dholmes : 7/13/1998
terry : 7/1/1998
dkim : 6/30/1998
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alopez : 5/21/1998
alopez : 1/12/1998
dholmes : 1/6/1998
dholmes : 11/5/1997
jenny : 10/21/1997
terry : 10/14/1997
terry : 10/13/1997
terry : 10/9/1997
mark : 8/12/1997
terry : 8/4/1997
alopez : 8/4/1997
terry : 7/31/1997
alopez : 7/10/1997
alopez : 7/10/1997
terry : 6/23/1997
alopez : 6/23/1997
terry : 6/23/1997
terry : 6/20/1997
joanna : 5/8/1997
alopez : 4/28/1997
alopez : 4/28/1997
alopez : 4/28/1997
alopez : 4/24/1997
alopez : 4/24/1997
terry : 4/23/1997
terry : 3/21/1997
terry : 3/17/1997
terry : 1/30/1997
terry : 1/30/1997
terry : 1/29/1997
terry : 1/27/1997
mark : 1/27/1997
mark : 1/21/1997
mark : 10/23/1996
carol : 9/26/1996
carol : 7/22/1996
carol : 7/22/1996
terry : 7/15/1996
terry : 7/12/1996
terry : 7/11/1996
mark : 6/19/1996
mark : 6/19/1996
mark : 6/19/1996
mark : 6/19/1996
mark : 6/7/1996
mark : 3/30/1996
mark : 3/21/1996
joanna : 3/20/1996
terry : 3/12/1996
mark : 3/12/1996
terry : 3/5/1996
mark : 2/1/1996
terry : 1/30/1996
mark : 12/13/1995
mark : 11/14/1995
terry : 10/25/1995
mimadm : 11/6/1994
jason : 7/19/1994
davew : 6/27/1994