Clinical characteristics.

KAT6B disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS) which are part of a broad phenotypic spectrum with variable expressivity; individuals presenting with a phenotype intermediate between GPS and SBBYSS have been reported. Both phenotypes are characterized by some degree of global developmental delay / intellectual disability; hypotonia; genital abnormalities; and skeletal abnormalities including patellar hypoplasia/agenesis, flexion contractures of the knees and/or hips, and anomalies of the digits, spine, and/or ribs. Congenital heart defects, small bowel malrotation, feeding difficulties, slow growth, cleft palate, hearing loss, and dental anomalies have been observed in individuals with either phenotype.

Diagnosis/testing.

The diagnosis of a KAT6B disorder is established by the identification of a heterozygous pathogenic variant in KAT6B on molecular genetic testing.

Management.

Treatment of manifestations: Medical problems associated with gastrointestinal, genitourinary, cardiac, palatal or dental anomalies; abnormal vision or lacrimal duct abnormality; hearing loss; or hypothyroidism associated with KAT6B disorders are treated or managed in the standard manner by the appropriate specialist. Referral to an early intervention program to access occupational, physical, speech, and feeding therapy beginning in infancy. Orthopedic intervention as needed for contractures and clubfoot; physical therapy to increase joint mobility.

Surveillance: Evaluations of developmental progress and educational needs, assessment for feeding issues, and monitoring for hearing loss, amblyopia, hypothyroidism, and contractures and/or scoliosis should occur annually. Evaluation and monitoring of cardiac malformation and/or renal function (if hydronephrosis or renal cysts are present) as needed.

Genetic counseling.

KAT6B disorders are inherited in an autosomal dominant manner. To date, most individuals with a KAT6B disorder have had a de novo pathogenic variant. Prenatal and preimplantation genetic testing are possible for families in which the pathogenic variant has been identified.

Suggestive Findings

A KAT6B disorder should be suspected in individuals with findings of either GPS or SBBYSS.

Genitopatellar syndrome (GPS). While clinical diagnostic criteria have not been defined for genitopatellar syndrome, the authors propose that the following features (Table 1) should raise suspicion for this disorder. Individuals with two major features or one major feature and two minor features are likely to have a KAT6B disorder.

Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome (SBBYSS). Clinical criteria for the diagnosis of SBBYSS [White et al 2003] have been expanded by the authors (Table 2) to prompt suspicion of SBBYSS. Individuals with two major features or one major feature and two minor features are likely to have a KAT6B disorder.

Establishing the Diagnosis

The diagnosis of a KAT6B disorder is established in a proband by identification of a heterozygous pathogenic variant in KAT6B by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of KAT6B disorders is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of a KAT6B disorder has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) are part of a broad phenotypic spectrum, and the variable expressivity of KAT6B disorders is being increasingly recognized. Individuals presenting with a phenotype intermediate between GPS and SBBYSS have been reported in the past years.

Genitopatellar Syndrome (GPS)

Skeletal features. Patellae are either absent or hypoplastic in the majority of individuals. In a minority, the patellae are dislocated but not hypoplastic. Note: In normal individuals, the patellae begin ossifying between ages 1.5 and four years in females and ages 2.5 and six years in males. Before that, they are cartilaginous and can be imaged by ultrasound.

Club feet and flexion contractures of the knees and/or hips are also present in nearly all individuals with GPS and constitute major features of this syndrome. This can significantly hinder mobility, especially since the knees in some cases cannot be extended beyond 90 degrees. Most of the musculoskeletal findings in GPS involve the lower extremities, but contractures of the wrists or elbows have also been observed in two affected individuals [Authors, personal observation].

Other skeletal anomalies are occasionally seen in affected individuals. Spinal anomalies resulting in thoracolumbar kyphoscoliosis have been observed in 11% of individuals reported in the literature. Some have thoracic anomalies such as narrow thorax, pectus excavatum, the presence of small cervical ribs, absence of a pair of ribs, and clavicular exostoses.

Pelvic anomalies include hip dislocations and hypoplasia of the iliac bone, ischia, and pubic rami.

Rare musculoskeletal findings include osteoporosis, radioulnar synostosis, radial head deformity, brachydactyly, camptodactyly, short stature, joint laxity, undertubulation of long bones, and coxa vara.

Neurologic features. Developmental delay and/or intellectual disability are noted in nearly all individuals diagnosed to date. The delay is global (motor and intellectual) and usually severe; some can communicate through vocalization, manipulate objects, and ambulate with walkers or tricycles. Behavioral and/or psychiatric issues (e.g., features suggestive of autism spectrum disorder, anxiety, aggressive behavior, and attention problems) have been noted.

Nearly all individuals with GPS have agenesis or hypoplasia of the corpus callosum. Seizures, cortical malformations, hydrocephaly, or ventriculomegaly have also been described in some affected individuals.

Some have hypotonia at birth, resulting in respiratory and feeding difficulties that can require invasive procedures (see Management). Laryngomalacia may exacerbate these difficulties. Both the feeding and respiratory difficulties often resolve in infancy; hypotonia of the extremities with hypertonia of the trunk has been described in older children.

Most have microcephaly, with occipitofrontal circumferences (OFCs) typically 2 SD (and occasionally 3 SD) below the mean.

Genital anomalies. Genitourinary anomalies are frequently present in individuals affected by GPS. In males, this can include cryptorchidism, retractile testis, scrotal hypoplasia, micropenis, unilateral testicular agenesis and hypospadias. Most females have clitoromegaly and/or hypoplasia of the labia (minora or majora). Delayed puberty with primary amenorrhea has also been reported [Okano et al 2018].

Renal anomalies. Many individuals affected by GPS have renal anomalies, especially hydronephrosis and multicystic kidneys. Renal anomalies resulting in renal failure and oligohydramnios sequence have been observed in three affected individuals who died in the neonatal period [Kim et al 2019; Authors, personal observation].

Anal anomalies. Anal atresia or stenosis and an anteriorly positioned anus are occasionally seen in GPS.

Facial features. Individuals with GPS can have bitemporal narrowing, prominent eyes (proptosis), and a nose with either a bulbous end or a broad or prominent base. Other features that can be common in both GPS and SBBYSS include low-set and posteriorly rotated ears, prominent cheeks, downslanting palpebral fissures, flat broad nasal bridge, long philtrum, thin upper lip, thin lip vermilion, and micro/retrognathia. See Figure 1.

Figure 1.

Photographs of 11 individuals with a KAT6B pathogenic variant Arrows point to the relative location of an individual's pathogenic variant in the schematic of the last KAT6B exon (exon 18), the distal part of which encodes the activation domain. Photographs (more...)

Cancer. Knight et al reported a child with GPS who developed a stage one neuroblastoma extending into the portal vein. While it was poorly differentiated, it had an overall favorable histopathology [Knight et al 2018].

Genotype-Phenotype Correlations

GPS. Most GPS-associated pathogenic variants cluster in KAT6B exon 18, the last exon, and are predicted to produce truncated proteins associated with a gain-of-function mechanism (see Molecular Genetics). Consistent with this hypothesis, pathogenic variants associated with more severe GPS phenotypes are located more proximally in exon 18 and are predicted to result in a more truncated protein.

SBBYSS. SBBYS-causing pathogenic variants also occur most frequently in exon 18, but more distally than the GPS-associated variants (Figure 1). Recently, predicted loss-of-function variants in exons 3, 7, 11, and 14-17 were reported to be associated with the SBBYSS phenotype.

Penetrance

Penetrance appears to be complete since all individuals reported to date who carry a KAT6B pathogenic variant present a phenotype compatible with KAT6B disorders.

Nomenclature

GPS. The term "genitopatellar syndrome" was coined by Valérie Cormier-Daire [Cormier-Daire et al 2000].

SBBYSS. Ohdo et al [1986] first described a family in which children had blepharophimosis, ptosis, congenital heart defects, intellectual disability, and hypoplastic teeth.

Subsequently, the Young-Simpson syndrome was described [Young & Simpson 1987]. Later the Young-Simpson syndrome was renamed the Say-Barber-Biesecker-Young-Simpson (SBBYS) variant of Ohdo syndrome (SBBYSS) [Say & Barber 1987, Biesecker 1991], which is discussed in this GeneReview.

Of note, the disorder described by Ohdo was distinct from the SBBYS variant of Ohdo syndrome because the facial features differed, proteinuria was present, and skeletal anomalies were absent; the mode of inheritance appeared to be autosomal recessive, autosomal dominant with reduced penetrance, or multifactorial.

Prevalence

The prevalence of KAT6B disorders is not known, but is estimated at fewer than one in a million individuals. To date, 89 individuals with molecularly confirmed KAT6B disorders have been reported in the literature, including 18 with GPS, 58 with SBBYSS, and 13 described as having an intermediate phenotype.

Other Disorders to Consider in the Differential Diagnosis

Dubowitz syndrome (OMIM 223370) is an autosomal recessive disorder of uncertain etiology consisting of blepharophimosis, ptosis, microcephaly, intellectual disability, growth restriction, and eczema (features variably present) [Tsukahara & Opitz 1996]. A Dubowitz-like syndrome was reported in a single family in association with biallelic pathogenic variants in NSUN2 [Martinez et al 2012].

Fetal alcohol spectrum disorders (FASD) associated with in utero alcohol can include blepharophimosis with short palpebral fissures, flat midface, long and smooth philtrum, thin vermilion of the upper lip, microcephaly, and intellectual disability. Various degrees and combinations of these features, along with a variety of birth defects, may be present in individuals with FASD. Affected individuals tend to have severe pre- and postnatal growth restriction, a finding more rarely observed in KAT6B disorders.

Toriello-Carey syndrome (agenesis of the corpus callosum with facial anomalies and Pierre Robin sequence) (OMIM 217980) shows multiple elements of overlap with KAT6B disorders: hypotonia, genital anomalies, microcephaly, agenesis of the corpus callosum, cleft palate, growth restriction, developmental delay and intellectual disability, ptosis, and congenital heart defects. Of note, Pierre Robin sequence is described as a cardinal manifestation of this disorder, whereas this sequence has been reported only in a small number of individuals with KAT6B disorders. However, Toriello-Carey syndrome is etiologically heterogeneous as different genetic alterations have been identified in individuals who are clinically suspected of having this disorder (various chromosomal deletions and pathogenic variants in PGAP3, DDX3X, and UBE3B). In one individual, a deleterious KAT6B variant has been identified [Dr John Carey, personal communication].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with KAT6B disorders, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Medical problems associated with gastrointestinal, genitourinary, cardiac, palatal, or dental anomalies; abnormal vision or lacrimal duct abnormality; hearing loss; or hypothyroidism associated with KAT6B disorders are treated or managed in the standard manner by the appropriate specialist. Other recommended treatments are listed below.

Surveillance

Evaluation of Relatives at Risk

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

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.

Mode of Inheritance

KAT6B disorders including genitopatellar syndrome (GPS) and Say-Barber-Biesecker variant of Ohdo syndrome (SBBYSS) are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with a KAT6B disorder have a de novo pathogenic variant.
• An individual diagnosed with a KAT6B disorder had an affected parent in at least three families.
  • Transmission of a KAT6B pathogenic variant in three generations of a family with SBBYSS has been reported [Kim et al 2017].
  • An inherited pathogenic variant has been found in individuals with mild SBBYSS phenotypes [Yates et al 2019; Authors, personal observation]
  • A woman with relatively mild SBBYSS had a child with classic SBBYSS [Mhanni et al 1998]; however, to the authors' knowledge molecular testing has not been performed in this family.
• If a KAT6B pathogenic variant has been identified in a proband, molecular genetic testing is recommended for the parents of the proband.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known KAT6B pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].

Offspring of a proband. Each child of an individual with a KAT6B disorder has a 50% chance of inheriting the KAT6B pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the KAT6B pathogenic variant, members of the parent's family may also be heterozygous for the pathogenic variant.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 couples who have had a child with a KAT6B disorder and young adults who are more mildly affected.

Prenatal Testing and Preimplantation Genetic Testing

Once the KAT6B pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for a KAT6B disorder are possible.

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

KAT6B encodes the highly conserved histone acetyltransferase KAT6B, which functions in a multi-subunit complex with other proteins including KAT6A, BRPF1, and ING5 [Yang 2015]. KAT6B chromatin remodeling through histone acetylation regulates the expression of multiple genes [Doyon et al 2006, Kraft et al 2011].

Mechanism of disease causation. GPS and SBBYSS are hypothesized to occur through a gain-of-function and loss-of-function disease mechanism, respectively. Pathogenic variants, which include nonsense, missense, splice site, and predicted frameshift variants, are most often located in exon 18, the last exon of the gene.

• GPS. Most pathogenic variants causing GPS cluster in KAT6B exon 18, the last exon, and are predicted to escape nonsense-mediated decay, resulting in a truncated protein causing disease via a gain-of-function mechanism. Consistent with this hypothesis, pathogenic variants causing the more severe GPS phenotype are located proximally in exon 18 and are believed to lead to the expression of a truncated protein lacking less of the C-terminal domain. A gain-of-function effect was hypothesized to occur from altered binding affinity or dysregulated interactions of KAT6B with its natural binding partners. This has not yet been tested experimentally.
• SBBYSS. SBBYSS-causing pathogenic variants occur throughout the gene are hypothesized to be loss-of-function variants. SBBYSS-associated variants occur most frequently in exon 18, but more distally than the GPS-associated variants (Figure 1). In addition, more proximal disease-associated variants in exons 3, 7, 11, and 14-17 have also been reported. The SBBYSS phenotype is hypothesized to result from the loss of KAT6B functions. This has not yet been tested experimentally.

KAT6B-specific laboratory technical considerations. KAT6B comprises 18 exons, the first two of which are untranslated. Three protein isoforms exist owing to alternative splice donor sites used for exon 8. NM_012330.3 represents the longest transcript and encodes the longest isoform.

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Author Notes

Dr Brendan Lee's website

Dr Philippe Campeau's website

About the Authors' research. The spectrum of our research program extends from gene identification in human disease, to correlating mechanisms of disease with normal biologic processes, to measuring and manipulating these pathways for diagnosis and treatment in humans and in animal models.

Revision History

• 2 January 2020 (ha) Comprehensive update posted live
• 10 January 2013 (cd) Revision: sequence analysis and prenatal diagnosis available clinically
• 13 December 2012 (me) Review posted live
• 19 June 2012 (pc/bl) Original submission