Clinical characteristics.

FLNA deficiency is associated with a phenotypic spectrum that includes FLNA-related periventricular nodular heterotopia (Huttenlocher syndrome), congenital heart disease (patent ductus arteriosus, atrial and ventricular septal defects), valvular dystrophy, dilatation and rupture of the thoracic aortic, pulmonary disease (pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis), gastrointestinal dysmotility and obstruction, joint hypermobility, and macrothrombocytopenia.

Diagnosis/testing.

The diagnosis of FLNA deficiency is established in a proband by identification of a heterozygous FLNA pathogenic variant in a female or a hemizygous FLNA pathogenic variant in a male.

Management.

Treatment of manifestations: Treatment of epilepsy generally follows principles for a seizure disorder caused by a known structural brain abnormality. Anti-seizure medication is typically selected based on specific attributes (e.g., teratogenic risk during pregnancy, tolerability, and efficacy). Standard treatment for aortic or carotid dissection, congenital heart disease, and valvular disease. Because of the risk for aortic or carotid dissection, ensure good blood pressure control. Good pulmonary toilet is recommended to preserve lung function. Sildenafil and medical management for pulmonary hypertension. Standard treatments for impaired bowel motility. Treatment of joint hypermobility as recommended by orthopedist, physical therapist, and/or occupational therapist. Treatment of bleeding diathesis per hematologist. If needed, early intervention services and special education support may be considered.

Surveillance: Monitor for seizures, constipation, joint issues, bleeding diathesis, and developmental issues at each visit. Cardiology evaluations, echocardiogram, stress testing, and cardiac MRI as recommended by cardiologist. Follow up with pulmonologist for any lung issues.

Evaluation of relatives at risk: Given the risk for vascular disease in neurologically asymptomatic individuals, it is appropriate to evaluate the older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from echocardiogram and cardiac MRI to screen for FLNA-associated structural heart disease and thoracic aortic aneurysms.

Pregnancy management: The teratogenic risk to the fetus associated with the use of anti-seizure medication during pregnancy depends on the type of anti-seizure medication used, the dose, and the gestational age of the fetus. There are currently no guidelines regarding the most appropriate surveillance for and management of cardiac, vascular, and connective tissue problems during pregnancy.

Genetic counseling.

FLNA deficiency is inherited in an X-linked manner. The condition is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female. About 50% of affected females inherit the pathogenic variant from their mother and at least 50% have a de novo pathogenic variant. For women with FLNA deficiency, the risk of passing the pathogenic variant to each child is 50%. Because of the high rate of prenatal lethality in males, most sons born to women with FLNA deficiency are unaffected. Prenatal diagnosis by molecular genetic testing is possible once the pathogenic variant has been identified in an affected family member. Periventricular nodules may be visualized by imaging as early as 24 weeks' gestation; however, the sensitivity of imaging for the prenatal detection of PVNH is not known.

Suggestive Findings

FLNA deficiency should be suspected in an individual with the following clinical features, neuroimaging findings, and family history. (Note: Affected males frequently show male lethality.)

Clinical features

• Seizure disorder
• Cardiovascular findings: dilated aortic root or thoracic ascending aorta, valvular heart disease, structural heart disease
• Pulmonary findings: pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis
• Gastrointestinal manifestations: feeding difficulties, constipation, progressive weight loss, congenital short bowel, chronic intestinal pseudo-obstruction
• Joint hypermobility

Neuroimaging features

• On brain MRI, bilateral, nearly contiguous periventricular nodular heterotopia (ectopic collections of neurons) lining the lateral ventricles beneath an otherwise normal-appearing cortex; occasionally, mild abnormalities of cerebral cortical gyri are present.
  Note: CT does not allow visualization of brain structures as clearly as MRI; therefore, heterotopia may be missed by CT imaging.
• Thinning of the corpus callosum and malformations of the posterior fossa (e.g., mild cerebellar hypoplasia, enlarged cisterna magna) in some individuals (See Figure 1.)

Figure 1.

Anatomic phenotype of PVNH in an individual with a heterozygous pathogenic variant in FLNA A. MRI of the head demonstrating characteristic periventricular nodular heterotopia

Family history consistent with X-linked inheritance with male lethality is strongly suggestive of FLNA deficiency.

Establishing the Diagnosis

Female proband. The diagnosis of FLNA deficiency is established in a female proband by identification of a heterozygous loss-of-function variant in FLNA on molecular genetic testing (see Table 1).

Male proband. Male lethality is common. However, the diagnosis of FLNA deficiency is established in a male proband by identification of a hemizygous loss-of-function variant in FLNA on molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing or use of a multigene panel:

• Single-gene testing. Sequence analysis of FLNA is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
• A multigene panel that includes FLNA and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

FLNA deficiency is prenatally or neonatally lethal in most males; therefore, the majority of affected individuals are female. To date, more than 100 individuals (both males and females) have been identified with loss-of-function variants in FLNA. The following description of the phenotypic features associated with this condition is based on these reports.

Seizure disorder. Approximately 88% of individuals (including males and females) with FLNA-related periventricular nodular heterotopia (PVNH) have presented with a seizure disorder [Guerrini & Carrozzo 2001]; in other series that included investigation of asymptomatic heterozygous mothers, the percentage was 63.3% [Lange et al 2015]. Many individuals are ascertained by MRI scan following a first seizure. As individuals are increasingly identified based on non-neurologic findings, a lower proportion of individuals with seizures will likely be confirmed. Age of seizure onset may be as early as the first years of life, but typically individuals present during childhood or adolescence, or even as adults, with an overall average age of seizure onset in the mid-teens [Fox et al 1998, Sheen et al 2001, Lange et al 2015]. The severity of the seizure disorder may range from mild (i.e., rare events, not requiring anti-seizure medication) to intractable seizures.

No correlation exists between the extent and severity of the nodular heterotopia seen radiographically and the clinical manifestations, though early seizure onset correlates with poorer developmental outcome [Lange et al 2015]. The ectopic heterotopias in some individuals act as foci for abnormal neuronal activity. Anatomic studies have shown aberrant projections extending from the periventricular heterotopias. Depth electrode recordings have demonstrated epileptogenic discharges from these nodules [Kothare et al 1998]. Thus, the seizure disorder appears to arise from the heterotopias in most individuals.

Cardiovascular findings. In a large cohort of 114 individuals from 80 families with loss-of-function FLNA variants and PVNH, 64.9% had a cardiovascular anomaly. Two thirds were structural cardiac defects, with patent ductus arteriosus, ventricular septal defects, and valve abnormalities being the most common [Chen et al 2018].

Almost 20% of individuals reported by Chen et al [2018] had thoracic aortic dilatation or aneurysm (TAA). Individuals with TAA typically had involvement of the aortic root and ascending aorta, and half of individuals with TAA had a sinus of Valsalva aneurysm [Feng et al 2006].

Isolated X-linked cardiac valvular dysplasia (XCVD) has been identified in individuals with FLNA missense variants associated with some retained FLNA function, typically resulting in myxomatous valvular dystrophy most commonly involving the mitral valve [Kyndt et al 2007, Le Tourneau et al 2018] although other valvular involvement was also noted. XCVD may necessitate cardiac surgery in some individuals. This phenotype was identified in individuals with one of three FLNA missense variants: p.Pro637Gln, p.His743Pro, or p.Gly288Arg. Affected males in the cohort had more severe valvular disease than females, who were sometimes unaffected [Le Tourneau et al 2018].

Pulmonary findings. Individuals with FLNA deficiency may develop varying degrees of pulmonary hypertension, which when severe has necessitated treatment with sildenafil. Several reported individuals (both male and female) had cardiorespiratory failure before age one year. The severity of the poorly defined respiratory disease, resembling bronchopulmonary dysplasia, has led to lung transplantation in several of these young children [Masurel-Paulet et al 2011, Clapham et al 2012, Lord et al 2014, Burrage et al 2017, Kremer et al 2019, Sasaki et al 2019].

Gastrointestinal manifestations. The spectrum of disease severity has ranged from constipation to chronic intestinal pseudo-obstruction (CIPO). Several individuals (primarily males), have been reported with delayed gastric motility [Negri et al 2020]. Clinical presentation typically includes feeding difficulties at birth, constipation, progressive weight loss, and congenital short bowel seen in isolation or in combination with intestinal malrotation [Oegema et al 2013]. Feeding issues may be present and improve with time, resolving after the first year of life. Conservative treatments including diet management were successful in some symptomatic older individuals [Oegema et al 2013]. Prolonged nutrition supplementation, gastrotomy, and/or jejunostomy tube feeding may be necessary in some individuals.

Males with FLNA loss-of-function variants have presented with severe abdominal wall defects, resulting in prune belly syndrome; characterized by: wrinkled, lax abdominal walls with partial or complete skeletal muscle deficiency; urinary tract dilatation with poorly contractile smooth muscle; and undescended testes [Iqbal et al 2020].

Isolated gastrointestinal manifestations. Loss-of-function FLNA variants have also been described as a cause of congenital short bowel syndrome in males and females. Males with X-linked congenital intestinal pseudo-obstruction (CIPO) have been found to have FLNA loss-of-function variants [van der Werf et al 2015, Negri et al 2020, Wade et al 2020]. CIPO includes reduced intestinal motility and a short, malrotated, and dilated small intestine. Severe intestinal dysmotility resulted in the need for long-term parenteral nutrition in several individuals [Jenkins et al 2018].

Joint hypermobility. In a case series of 47 individuals (2 males, 45 females) with FLNA-related PVNH, 14.7% presented with joint laxity. Joint dislocation can also occur, involving the hips and other joints [Lange et al 2015].

Skin abnormalities. Cutis laxa, hyperextensibility, and thin, soft, or translucent skin [Reinstein et al 2013, Ritelli et al 2017] may also be present, occurring independently or in combination.

Shortened digits. Some individuals are reported to have hypoplasia of the distal phalanges in general or of the great toe, or short proximal thumbs.

Macrothrombocytopenia. Individuals with FLNA deficiency can present with large platelets that may also be reduced in number, resulting in excessive bruising, bleeding, and slow wound healing [Nurden et al 2011]. Macrothombocytopenia can occur with missense, deletion, exon-skipping [Oda et al 2016], or truncation variants of FLNA. Isolated macrothrombocytopenia was reported in an individual with thrombocytopenia, bleeding, and an FLNA missense variant (p.Glu1795Lys) without other features of FLNA deficiency [Nurden et al 2011].

Cognitive function / dyslexia. Intelligence is normal to borderline. Formal cognitive testing of ten affected individuals (2 males, 8 females) with FLNA loss-of-function variants demonstrated an average IQ of 95, but also a strikingly high number of affected individuals with dyslexia [Chang et al 2005, Chang et al 2007, Reinstein et al 2012]. However, these results likely reflect a selection bias towards more severely affected individuals, since those with normal cognitive function usually would not have undergone a screening brain MRI or molecular testing.

Pregnancy complications. Women with FLNA deficiency may have an increased incidence of pregnancy loss as a result of spontaneous abortion of affected male pregnancies.

Other

• Immune compromise with recurrent infection was reported in two individuals
• Overwhelming hemorrhage and arrested myeloid and erythroid bone marrow development was reported in one male [Huttenlocher et al 1994].
• Bilateral inguinal hernia has been reported in affected males [Oegema et al 2013, Ritelli et al 2017]

Mosaicism. Somatic mosaicism for an A>G substitution at the intron 11 acceptor splice site was reported by Parrini et al [2004] in a male with bilateral PVNH. Sequence analysis and denaturing high-performance liquid chromatography of genomic DNA on a pool of hair roots, single hair roots, and white blood cells revealed that only 42% and 69% of the samples for hair and blood, respectively, had the pathogenic variant. Moreover, the affected male's daughter did not inherit the pathogenic variant, thought to be causal for the male phenotype. Other somatic pathogenic variants were subsequently reported [Jamuar et al 2014, González-Morón et al 2017].

Genotype-Phenotype Correlations

p.Pro637Gln, p.His743Pro, and p.Gly288Arg have been associated with isolated X-linked cardiac valvular dysplasia [Kyndt et al 2007, Le Tourneau et al 2018]. Affected males were found to have more severe valvular disease [Le Tourneau et al 2018].

Females with PVNH typically have FLNA variants predicted to cause severe loss of function (e.g., nonsense, frameshift, and severe splicing variants) throughout the gene or missense variants in the N-terminal actin-binding domain [Walsh & Engle 2010, Lange et al 2015].

Surviving affected males. Nonsense variants in surviving males often affect the C terminus of the protein, consistent with partial loss of function, while missense variants in surviving males can be scattered throughout the gene [Walsh & Engle 2010, Lange et al 2015, Chen et al 2018]. Presumably, these pathogenic variants lead to a partially functional protein [Sheen et al 2001].

Penetrance

All individuals with known deleterious loss-of-function FLNA variants typically have shown periventricular nodular heterotopia. Penetrance for other phenotypes has not been determined.

Nomenclature

The authors suggest the term Huttenlocher syndrome for individuals with FLNA deficiency and multi-system involvement.

Prevalence

The prevalence of FLNA deficiency is difficult to assess because individuals with the mild phenotype may never seek medical evaluation.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with FLNA deficiency, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Management of individuals with FLNA deficiency is directed toward symptomatic treatment.

Surveillance

Evaluation of Relatives at Risk

Given the risk for vascular disease in neurologically asymptomatic individuals, it is appropriate to clarify the genetic status of older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from echocardiogram and MRI/MRA to screen for FLNA-associated cardiovascular problems (see Surveillance).

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Ideally, women should seek information prior to conception regarding risks to the fetus associated with taking an anti-seizure medication during pregnancy so that changes in the anti-seizure medication regimen (if needed) can be made prior to conception. If not done prior to conception, discussion of the risks and benefits of anti-seizure medication use during pregnancy should occur as soon as the pregnancy is recognized. The teratogenic risk to the fetus associated with the use of anti-seizure medication during pregnancy depends on the type of anti-seizure medication used, the dose, and the gestational age of the fetus.

Women with FLNA deficiency may have an increased incidence of pregnancy loss as a result of spontaneous abortion of affected male pregnancies. Currently no guidelines exist on the most appropriate surveillance for and management of cardiac, vascular, and connective tissue problems during pregnancy in women with PVNH. See Marfan Syndrome and Classic Ehlers-Danlos Syndrome for possible pregnancy management recommendations.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Surgical resection has been attempted but has not proven beneficial [Li et al 1997].

Mode of Inheritance

FLNA deficiency is inherited in an X-linked manner.

• FLNA-related periventricular nodular heterotopia (PVNH). Affected individuals are predominantly females with severe loss-of-function variants. Males often show early lethality, though some males with mosaic pathogenic variants or variants resulting in partial loss of function survive.
• Isolated X-linked cardiac valvular dysplasia (XCVD) and FLNA-related isolated gastrointestinal manifestations. Affected individuals are typically male. Heterozygous female family members may or may not be affected.
• Isolated macrothrombocytopenia has been reported in several heterozygous females [Nurden et al 2011].

Risk to Family Members

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have an FLNA pathogenic variant.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the FLNA pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Ultrasound examination. Fetal ultrasound is relatively insensitive at detecting PVNH until late into the second trimester in pregnancy. PVNH may be detected by fetal ultrasound examination or MRI as early as 20-24 weeks' gestation. Fetal MRI is performed at some centers using ultrafast MRI so that sedation is not required to reduce fetal movement. The sensitivity of prenatal imaging for the detection of PVNH is not known. Whether PVNH may be detected even earlier in gestation by imaging studies is not known.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The filamin class of actin-binding proteins is known to regulate cell stability, protrusion, motility, cell-cell communication, and response to stress across various biologic systems [Leonardi et al 2000, Stahlhut & van Deurs 2000, Feng & Walsh 2004]. Filamin-deficient melanocytes fail to undergo locomotion in response to factors that elicit migration in the same filamin-expressing cells. They exhibit prolonged circumferential blebbing, abnormal phagocytosis, and impaired volume regulation, perhaps secondary to abnormal regulation of sodium channel activity.

FLNA encodes a cytoplasmic actin-binding phosphoprotein that links membrane receptors to the actin cytoskeleton and represents a potentially crucial link between signal transduction and the cytoskeleton. Findings suggest that filamin A may have a role in adherens junctions that line the ventricle, with defects in FLNA disrupting the ventricular lining and neuroepithelial architecture, causing failure of neuronal migration [Zhang et al 2016].

Mechanism of disease causation. Loss of function; typically heterozygous null variants in affected females and missense or mosaic variants in mildly affected females and rare affected males [Wade et al 2020]

FLNA-specific laboratory technical considerations. FLNA contains 46 coding exons as well as a “poison exon” between exons 9 and 10 that encodes a premature termination codon, which is utilized in a cell type-specific pattern. This poison exon is excluded in brain stem cells but is included in neurons resulting in loss of filamin A function. Pathogenic variants affecting the splice sites regulating this poison exon cause loss of function because of abnormal inclusion of the poison exon [Zhang et al 2016]. FLNA shows at least two transcriptional start sites, one of which creates a protein longer than the canonic protein by 28 amino acid residues added at the N terminus. Loss-of-function variants restricted to this longer transcript cause CIP with normal heart and brain development, indicating that the longer splice form has preferential roles in gut development [Wade et al 2020]. Other exons show preferential utilization in heart versus brain [Zhang et al 2016]. The locus has very high GC content, making it difficult to amplify by PCR or to sequence either by Sanger or next-generation sequencing.

Author Notes

Ming Hui Chen, MD, MMSc is an Associate Professor of Pediatrics at Harvard Medical School in the Departments of Cardiology and Pediatrics, and the Division of Genetics and Genomics at Boston Children's Hospital, Boston, MA. Dr Chen is an expert in cardiovascular and medical manifestations of FLNA pathogenic variants. She follows a large cohort of patients and families with PVNH and FLNA pathogenic variants. Dr Chen is the Founder and Director of the Cardiology Clinic for Brain Development in Genetics (C-BrDG), a specialized FLNA-PVNH clinic at Boston Children’s Hospital. For further information regarding clinical care and clinical research in individuals with PVNH and FLNA deficiencies, please visit our website at mhchenlab.org or email cbridge@childrens.harvard.edu.

Dr Chen has worked very closely over the last two decades with Dr Christopher A Walsh, MD, PhD, who is the Chief of Genetics and Genomics at Boston Children's Hospital, and the Bullard Professor of Pediatrics and Neurology at Harvard Medical School. The Walsh lab has worked on genetic disorders affecting the human cerebral cortex for more than twenty years, publishing twenty papers on PVNH, FLNA, and related disorders.

Acknowledgments

We are grateful to patients with PVNH and other brain disorders, their physicians, and to many colleagues present and past for collaborating with us to understand the genetic basis of these conditions, and for the patient support groups that we have allied with to help understand and develop better therapies.

Research on PVNH in the Chen group and the Walsh lab has been supported by grant funding from the NIH and the NINDS (R01 NS 35129). CAW is an Investigator of the Howard Hughes Medical Institute.

Author History

Adria Bodell, MS, CGC; Beth Israel Deaconess Medical Center (2007-2015)
Ming Hui Chen, MD, MMSc (2015-present)
Volney L Sheen, MD, PhD; Harvard Medical School (2007-2015)
Christopher A Walsh, MD, PhD (2007-present)

Revision History

• 30 September 2021 (sw) Comprehensive update posted live
• 17 September 2015 (me) Comprehensive update posted live
• 11/10/2014 (cw/mhc) Revision: cardiovascular added, other modifications made
• 4 June 2009 (cd/cw) Revision: deletion/duplication analysis available; mutation added; Differential Diagnosis edited
• 10 April 2007 (me) Comprehensive update posted live
• 4 August 2004 (me) Comprehensive update posted live
• 21 January 2004 (cd) Revision: testing
• 17 October 2003 (cw) Revision: Genetically Related Disorders
• 8 October 2002 (me) Review posted live
• 29 April 2002 (cw) Original submission

Literature Cited

• Burrage LC, Guillerman RP, Das S, Singh S, Schady DA, Morris SA, Walkiewicz M, Schecter MG, Heinle JS, Lotze TE, Lalani SR, Mallory GB. Lung transplantation for FLNA-associated progressive lung disease. J Pediatr. 2017;186:118–23.e6. [PMC free article: PMC5534178] [PubMed: 28457522]
• Chang BS, Katzir T, Liu T, Corriveau K, Barzillai M, Apse KA, Bodell A, Hackney D, Alsop D, Wong ST, Walsh CA. A structural basis for reading fluency: white matter defects in a genetic brain malformation. Neurology. 2007;69:2146–54. [PubMed: 18056578]
• Chang BS, Ly J, Appignani B, Bodell A, Apse KA, Ravenscroft RS, Sheen VL, Doherty MJ, Hackney DB, O'Connor M, Galaburda AM, Walsh CA. Reading impairment in the neuronal migration disorder of periventricular nodular heterotopia. Neurology. 2005;64:799–803. [PubMed: 15753412]
• Chen MH, Choudhury S, Hirata M, Khalsa S, Chang B, Walsh CA. Thoracic aortic aneurysm in patients with loss of function Filamin A mutations: Clinical characterization, genetics, and recommendations. Am J Med Genet A. 2018;176:337–50. [PMC free article: PMC7534149] [PubMed: 29334594]
• Clapham KR, Yu TW, Ganesh VS, Barry B, Chan Y, Mei D, Parrini E, Funalot B, Dupuis L, Nezarati MM, du Souich C, van Karnebeek C, Guerrini R, Walsh CA. FLNA genomic rearrangements cause periventricular nodular heterotopia. Neurology. 2012;78:269–78. [PMC free article: PMC3280053] [PubMed: 22238415]
• Clayton-Smith J, Walters S, Hobson E, Burkitt-Wright E, Smith R, Toutain A, Amiel J, Lyonnet S, Mansour S, Fitzpatrick D, Ciccone R, Ricca I, Zuffardi O, Donnai D. Xq28 duplication presenting with intestinal and bladder dysfunction and a distinctive facial appearance. Eur J Hum Genet. 2009;17:434–43. [PMC free article: PMC2986219] [PubMed: 18854860]
• de Wit MC, de Coo IF, Halley DJ, Lequin MH, Mancini GM. Movement disorder and neuronal migration disorder due to ARFGEF2 mutation. Neurogenetics. 2009;10:333–6. [PMC free article: PMC2758209] [PubMed: 19384555]
• Dobyns WB, Guerrini R, Czapansky-Beilman DK, Pierpont ME, Breningstall G, Yock DH Jr, Bonanni P, Truwit CL. Bilateral periventricular nodular heterotopia with mental retardation and syndactyly in boys: a new X-linked mental retardation syndrome. Neurology. 1997;49:1042–7. [PubMed: 9339687]
• Feng Y, Chen MH, Moskowitz IP, Mendonza AM, Vidali L, Nakamura F, Kwiatkowski DJ, Walsh CA, Filamin A. FLNA) is required for cell-cell contact in vascular development and cardiac morphogenesis. Proc Natl Acad Sci U S A. 2006;103:19836–41. [PMC free article: PMC1702530] [PubMed: 17172441]
• Feng Y, Walsh CA. The many faces of filamin: a versatile molecular scaffold for cell motility and signalling. Nat Cell Biol. 2004;6:1034–8. [PubMed: 15516996]
• Fox JW, Lamperti ED, Ekşioğlu YZ, Hong SE, Feng Y, Graham DA, Scheffer IE, Dobyns WB, Hirsch BA, Radtke RA, Berkovic SF, Huttenlocher PR, Walsh CA. Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia. Neuron. 1998;21:1315–25. [PubMed: 9883725]
• González-Morón D, Vishnopolska S, Consalvo D, Medina N, Marti M, Córdoba M, Vazquez-Dusefante C, Claverie S, Rodríguez-Quiroga SA, Vega P, Silva W, Kochen S, Kauffman MA. Germline and somatic mutations in cortical malformations: molecular defects in Argentinean patients with neuronal migration disorders. PLoS One. 2017;12:e0185103. [PMC free article: PMC5617183] [PubMed: 28953922]
• Guerrini R, Carrozzo R. Epileptogenic brain malformations: clinical presentation, malformative patterns and indications for genetic testing. Seizure. 2001;10:532–43. [PubMed: 11749114]
• Heinzen EL, O'Neill AC, Zhu X, Allen AS, Bahlo M, Chelly J, Chen MH, Dobyns WB, Freytag S, Guerrini R, Leventer RJ, Poduri A, Robertson SP, Walsh CA, Zhang M. Epi4K Consortium; Epilepsy Phenome/Genome Project. De novo and inherited private variants in MAP1B in periventricular nodular heterotopia. PLoS Genet. 2018;14:e1007281. [PMC free article: PMC5965900] [PubMed: 29738522]
• Huttenlocher PR, Taravath S, Mojtahedi S. Periventricular heterotopia and epilepsy. Neurology. 1994;44:51–5. [PubMed: 8290091]
• Iqbal NS, Jascur TA, Harrison SM, Edwards AB, Smith LT, Choi ES, Arevalo MK, Chen C, Zhang S, Kern AJ, Scheuerle AE, Sanchez EJ, Xing C, Baker LA. Prune belly syndrome in surviving males can be caused by Hemizygous missense mutations in the X-linked Filamin A gene. BMC Med Genet. 2020;21:38. [PMC free article: PMC7035669] [PubMed: 32085749]
• Jamuar SS, Lam AT, Kircher M, D'Gama AM, Wang J, Barry BJ, Zhang X, Hill RS, Partlow JN, Rozzo A, Servattalab S, Mehta BK, Topcu M, Amrom D, Andermann E, Dan B, Parrini E, Guerrini R, Scheffer IE, Berkovic SF, Leventer RJ, Shen Y, Wu BL, Barkovich AJ, Sahin M, Chang BS, Bamshad M, Nickerson DA, Shendure J, Poduri A, Yu TW, Walsh CA. Somatic mutations in cerebral cortical malformations. N Engl J Med. 2014;371:733–43. [PMC free article: PMC4274952] [PubMed: 25140959]
• Jenkins ZA, Macharg A, Chang CY, van Kogelenberg M, Morgan T, Frentz S, Wei W, Pilch J, Hannibal M, Foulds N, McGillivray G, Leventer RJ, García-Miñaúr S, Sugito S, Nightingale S, Markie DM, Dudding T, Kapur RP, Robertson SP. Differential regulation of two FLNA transcripts explains some of the phenotypic heterogeneity in the loss-of-function filaminopathies. Hum Mutat. 2018;39:103–13. [PubMed: 29024177]
• Kothare SV, VanLandingham K, Armon C, Luther JS, Friedman A, Radtke RA. Seizure onset from periventricular nodular heterotopias: depth-electrode study. Neurology. 1998;51:1723–7. [PubMed: 9855532]
• Kremer TM, Lindsay ME, Kinane TB, Hawley MH, Little BP, Mino-Kenudson M. Case 28-2019: A 22-year-old woman with dyspnea and chest pain. N Engl J Med. 2019;381:1059–67. [PubMed: 31509678]
• Kyndt F, Le Scouarnec S, Jaafar P, Gueffet JP, Legendre A, Trochu JN, Jousseaume V, Chaventré A, Schott JJ, Le Marec H, Probst V. Genetic aspects of valvulopathies. Arch Mal Coeur Vaiss. 2007;100:1013–20. [PubMed: 18223515]
• Lange M, Kasper B, Bohring A, Rutsch F, Kluger G, Hoffjan S, Spranger S, Behnecke A, Ferbert A, Hahn A, Oehl-Jaschkowitz B, Graul-Neumann L, Diepold K, Schreyer I, Bernhard MK, Mueller F, Siebers-Renelt U, Beleza-Meireles A, Uyanik G, Janssens S, Boltshauser E, Winkler J, Schuierer G, Hehr U. 47 patients with FLNA associated periventricular nodular heterotopia. Orphanet J Rare Dis. 2015;10:134. [PMC free article: PMC4608144] [PubMed: 26471271]
• Le Tourneau T, Le Scouarnec S, Cueff C, Bernstein D, Aalberts JJJ, Lecointe S, Mérot J, Bernstein JA, Oomen T, Dina C, Karakachoff M, Desal H, Al Habash O, Delling FN, Capoulade R, Suurmeijer AJH, Milan D, Norris RA, Markwald R, Aikawa E, Slaugenhaupt SA, Jeunemaitre X, Hagège A, Roussel JC, Trochu JN, Levine RA, Kyndt F, Probst V, Le Marec H, Schott JJ. New insights into mitral valve dystrophy: a Filamin-A genotype-phenotype and outcome study. Eur Heart J. 2018;39:1269–77. [PMC free article: PMC5905589] [PubMed: 29020406]
• Leonardi A, Ellinger-Ziegelbauer H, Franzoso G, Brown K, Siebenlist U. Physical and functional interaction of filamin (actin-binding protein-280) and tumor necrosis factor receptor-associated factor 2. J Biol Chem. 2000;275:271–8. [PubMed: 10617615]
• Li LM, Dubeau F, Andermann F, Fish DR, Watson C, Cascino GD, Berkovic SF, Moran N, Duncan JS, Olivier A, Leblanc R, Harkness W. Periventricular nodular heterotopia and intractable temporal lobe epilepsy: poor outcome after temporal lobe resection. Ann Neurol. 1997;41:662–8. [PubMed: 9153529]
• Lord A, Shapiro AJ, Saint-Martin C, Claveau M, Melançon S, Wintermark P. Filamin A mutation may be associated with diffuse lung disease mimicking bronchopulmonary dysplasia in premature newborns. Respir Care. 2014;59:e171–7. [PubMed: 25053830]
• Masurel-Paulet A, Haan E, Thompson EM, Goizet C, Thauvin-Robinet C, Tai A, Kennedy D, Smith G, Khong TY, Solé G, Guerineau E, Coupry I, Huet F, Robertson S, Faivre L. Lung disease associated with periventricular nodular heterotopia and an FLNA mutation. Eur J Med Genet. 2011;54:25–8. [PubMed: 20888935]
• Moro F, Pisano T, Bernardina BD, Polli R, Murgia A, Zoccante L, Darra F, Battaglia A, Pramparo T, Zuffardi O, Guerrini R. Periventricular heterotopia in fragile X syndrome. Neurology. 2006;67:713–5. [PubMed: 16924033]
• Negri E, Coletta R, Morabito A. Congenital short bowel syndrome: systematic review of a rare condition. J Pediatr Surg. 2020;55:1809–14. [PubMed: 32278545]
• Nurden P, Debili N, Coupry I, Bryckaert M, Youlyouz-Marfak I, Solé G, Pons AC, Berrou E, Adam F, Kauskot A, Lamazière JM, Rameau P, Fergelot P, Rooryck C, Cailley D, Arveiler B, Lacombe D, Vainchenker W, Nurden A, Goizet C. Thrombocytopenia resulting from mutations in filamin A can be expressed as an isolated syndrome. Blood. 2011;118:5928–37. [PubMed: 21960593]
• Oda H, Sato T, Kunishima S, Nakagawa K, Izawa K, Hiejima E, Kawai T, Yasumi T, Doi H, Katamura K, Numabe H, Okamoto S, Nakase H, Hijikata A, Ohara O, Suzuki H, Morisaki H, Morisaki T, Nunoi H, Hattori S, Nishikomori R, Heike T. Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function. Eur J Hum Genet. 2016;24:408–14. [PMC free article: PMC4755370] [PubMed: 26059841]
• Oegema R, Hulst JM, Theuns-Valks SD, van Unen LM, Schot R, Mancini GM, Schipper ME, de Wit MC, Sibbles BJ, de Coo IF, Nanninga V, Hofstra RM, Halley DJ, Brooks AS. Novel no-stop FLNA mutation causes multi-organ involvement in males. Am J Med Genet A. 2013;161A:2376–84. [PubMed: 23873601]
• Parrini E, Mei D, Wright M, Dorn T, Guerrini R. Mosaic mutations of the FLN1 gene cause a mild phenotype in patients with periventricular heterotopia. Neurogenetics. 2004;5:191–6. [PubMed: 15459826]
• Parrini E, Ramazzotti A, Dobyns WB, Mei D, Moro F, Veggiotti P, Marini C, Brilstra EH, Dalla Bernardina B, Goodwin L, Bodell A, Jones MC, Nangeroni M, Palmeri S, Said E, Sander JW, Striano P, Takahashi Y, Van Maldergem L, Leonardi G, Wright M, Walsh CA, Guerrini R. Periventricular heterotopia: phenotypic heterogeneity and correlation with Filamin A mutations. Brain. 2006;129:1892–906. [PubMed: 16684786]
• Reinstein E, Chang BS, Robertson SP, Rimoin DL, Katzir T. Filamin A mutation associated with normal reading skills and dyslexia in a family with periventricular heterotopia. Am J Med Genet A. 2012;158A:1897–901. [PubMed: 22740120]
• Reinstein E, Frentz S, Morgan T, García-Miñaúr S, Leventer RJ, McGillivray G, Pariani M, van der Steen A, Pope M, Holder-Espinasse M, Scott R, Thompson EM, Robertson T, Coppin B, Siegel R, Bret Zurita M, Rodríguez JI, Morales C, Rodrigues Y, Arcas J, Saggar A, Horton M, Zackai E, Graham JM, Rimoin DL, Robertson SP. Vascular and connective tissue anomalies associated with X-linked periventricular heterotopia due to mutations in Filamin A. Eur J Hum Genet. 2013;21:494–502. [PMC free article: PMC3641385] [PubMed: 23032111]
• Ritelli M, Morlino S, Giacopuzzi E, Carini G, Cinquina V, Chiarelli N, Majore S, Colombi M, Castori M. Ehlers-Danlos syndrome with lethal cardiac valvular dystrophy in males carrying a novel splice mutation in FLNA. Am J Med Genet A. 2017;173:169–76. [PubMed: 27739212]
• Sasaki E, Byrne AT, Phelan E, Cox DW, Reardon W. A review of filamin A mutations and associated interstitial lung disease. Eur J Pediatr. 2019;178:121–9. [PubMed: 30547349]
• Sheen VL, Dixon PH, Fox JW, Hong SE, Kinton L, Sisodiya SM, Duncan JS, Dubeau F, Scheffer IE, Schachter SC, Wilner A, Henchy R, Crino P, Kamuro K, DiMario F, Berg M, Kuzniecky R, Cole AJ, Bromfield E, Biber M, Schomer D, Wheless J, Silver K, Mochida GH, Berkovic SF, Andermann F, Andermann E, Dobyns WB, Wood NW, Walsh CA. Mutations in the X-linked filamin 1 gene cause periventricular nodular heterotopia in males as well as in females. Hum Mol Genet. 2001;10:1775–83. [PubMed: 11532987]
• Sheen VL, Ganesh VS, Topcu M, Sebire G, Bodell A, Hill RS, Grant PE, Shugart YY, Imitola J, Khoury SJ, Guerrini R, Walsh CA. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat Genet. 2004;36:69–76. [PubMed: 14647276]
• Sheen VL, Topçu M, Berkovic S, Yalnizoglu D, Blatt I, Bodell A, Hill RS, Ganesh VS, Cherry TJ, Shugart YY, Walsh CA. Autosomal recessive form of periventricular heterotopia. Neurology. 2003;60:1108–12. [PubMed: 12682315]
• Stahlhut M, van Deurs B. Identification of filamin as a novel ligand for caveolin-1: evidence for the organization of caveolin-1-associated membrane domains by the actin cytoskeleton. Mol Biol Cell. 2000;11:325–37. [PMC free article: PMC14777] [PubMed: 10637311]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• van der Werf CS, Halim D, Verheij JB, Alves MM, Hofstra RM. Congenital short bowel syndrome: from clinical and genetic diagnosis to the molecular mechanisms involved in intestinal elongation. Biochim Biophys Acta. 2015;1852:2352–61. [PubMed: 26282049]
• Wade EM, Halliday BJ, Jenkins ZA, O'Neill AC, Robertson SP. The X-linked filaminopathies: Synergistic insights from clinical and molecular analysis. Hum Mutat. 2020;41:865–83. [PubMed: 32108395]
• Walsh CA, Engle EC. Allelic diversity in human developmental neurogenetics: insights into biology and disease. Neuron. 2010;68:245–53. [PMC free article: PMC3010396] [PubMed: 20955932]
• Zhang X, Chen MH, Wu X, Kodani A, Fan J, Doan R, Ozawa M, Ma J, Yoshida N, Reiter JF, Black DL, Kharchenko PV, Sharp PA, Walsh CA. Cell-type-specific alternative splicing governs cell fate in the developing cerebral cortex. Cell. 2016;166:1147–62.e15. [PMC free article: PMC5248659] [PubMed: 27565344]