Kat6b Disorders
Summary
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.
Diagnosis
KAT6B disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker variant of Ohdo syndrome (Say-Barber-Biesecker-Young-Simpson syndrome; SBYSS).
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.
Table 1.
Features Suggestive of GPS
| Category | Features |
|---|---|
| Major features |
|
| Minor features |
|
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.
Table 2.
Features suggestive of Ohdo/SBBYS Syndrome (SBBYSS)
| Category | Features |
|---|---|
| Major features |
|
| Minor features |
|
Establishing the Diagnosis
The diagnosis of a KAT6B disorder is established in a proband with the 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).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of a KAT6B disorder, molecular genetic testing approaches can include single-gene testing or use of a multigene panel.
- Single-gene testing. Sequence analysis of KAT6B is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
- A multigene panel that includes KAT6B and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. (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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the diagnosis of a KAT6B disorder is not considered because an individual has atypical or nonspecific phenotypic features, comprehensive genomic testing (which does not require the clinician to determine which gene is likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 3.
Molecular Genetic Testing Used in KAT6B disorders
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| KAT6B | Sequence analysis 3 | >98% 4 |
| Gene-targeted deletion/duplication analysis 5 | 1 deletion reported 6, 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Gannon et al [2015], Radvanszky et al [2017]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Preiksaitiene et al [2017] and Herriges et al [2019]) may not be detected by these methods.
- 6.
A 5-Mb 10q22.1q22.3 deletion encompassing KAT6B has been described in an individual with a phenotype compatible with SBBYSS [Preiksaitiene et al 2017].
- 7.
Interstitial 10q21.3q22.2 deletions encompassing KAT6B have been reported in eight individuals who presented with some features overlapping with KAT6B disorders, such as hypotonia, developmental delay, feeding difficulties, and craniofacial dysmorphisms [Herriges et al 2019].
Note: One individual had a "Noonan syndrome-like" phenotype resulting from a translocation interrupting intron 3 of KAT6B [Kraft et al 2011].
Clinical Characteristics
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].
Say-Barber-Biesecker-Young-SImpson Variant of Ohdo Syndrome (SBBYSS)
Neurologic features. Affected individuals generally have some degree of developmental delay and/or intellectual disability. Milder cases have recently been described, where the pathogenic variant was inherited from an affected parent [Kim et al 2017, Yates et al 2019]. A language disorder is present in many affected individuals. Behavioral and/or psychiatric issues such as features suggestive of autism spectrum disorder, anxiety, aggressive behavior, and attention problems have been noted. A few affected individuals have agenesis or hypoplasia of the corpus callosum or other cerebral anomalies. 36% of reported cases have microcephaly.
Some neonates have hypotonia, with feeding and respiratory difficulties requiring hospitalization.
Ocular anomalies. Visual deficits and a variety of ocular anomalies have been reported in a large number of affected individuals. Blepharophimosis is a major feature of SBBYSS and it can impact visual function. Lacrimal duct anomalies, mainly dacryostenosis, are found in many individuals with SBBYSS and with an intermediate phenotype. Cortical visual impairment, optic atrophy or hypoplasia has also been described. Myopia and amblyopia are common. Telecanthus, epicanthus inversus, and hypertelorism are also sometimes noted
Skeletal features. Most individuals have long thumbs and great toes. Other digital malformations have been observed, including preaxial or postaxial polydactyly, camptodactyly, clinodactyly, bradydactyly, and syndactyly of toes. Some have patellar anomalies similar to those seen in GPS (i.e., aplasia or hypoplasia). Club feet and flexion contractures of the knees and/or hips are occasionally observed in some individuals.
Genital anomalies. Genital anomalies including cryptorchidism, hypospadias, clitoromegaly, and/or hypoplasia of the labia minora or majora are observed in approximately 40% of reported affected individuals with the SBBYSS phenotype.
Facial features. Facial appearance is distinctive with a mask-like facies, blepharophimosis, and ptosis. Other features that can be common in both GPS and SBBYSS include prominent cheeks, low-set and posteriorly rotated ears, downslanting palpebral fissures, flat broad nasal bridge, tubular/bulbous nose, long philtrum, thin upper lip, thin lip vermilion, and micro-/retrognathia. See Figure 1.
Other Features Observed in Individuals with Either the GPS or SBBYSS Phenotype
More than 50% of individuals with KAT6B disorders have congenital heart defects. These include mainly atrial and/or ventricular septal defects, patent foramen ovale and patent ductus arteriosus.
Small bowel malrotation has been described in eight affected individuals [Campeau et al 2012a; Gannon et al 2015; Okano et al 2018; Authors, personal observation].
Most affected individuals present with feeding difficulties and pathologic gastroesophageal reflux.
Growth restriction, short stature, failure to thrive/poor weight gain and delayed bone age have been reported in 18% of affected individuals.
Cleft palate has been reported in one third of affected individuals [Clayton-Smith et al 2011]. Pierre Robin sequence (defined as microretrognathia, glossoptosis, and cleft palate) has previously been observed in five affected individuals [Lonardo et al 2019; Authors, personal observation].
Bilateral hearing loss, both conductive and sensorineural, is often present.
Occasional dental anomalies including natal teeth, absent/hypoplastic teeth, retained primary dentition, and delayed eruption of teeth are mostly seen in in individuals with SBBYSS.
A minority of individuals have hypothyroidism – some of them having thyroid agenesis or hypoplasia.
Polyhydramnios can complicate the pregnancy of fetuses affected with KAT6B disorders. Increased nuchal translucency and/or cystic hygroma have also been observed in four affected individuals [Authors, personal observation].
Sagittal craniosynostosis was noted in two individuals with the intermediate phenotype [Bashir et al 2017]
Cutaneous manifestations are rarely observed in individuals with KAT6B disorders. Abnormal palmar creases, widely spaced nipples, hypoplastic nails, and café au lait macules have been reported in a few affected individuals.
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.
Differential Diagnosis
Table 4.
Genes of Interest in the Differential Diagnosis of KAT6B Disorders
| Gene(s) | Differential Diagnosis Disorder | MOI | Clinical Features of Differential Diagnosis Disorder | |
|---|---|---|---|---|
| Overlapping w/KAT6B Disorders | Not Observed in KAT6B Disorders | |||
| CDC45 CDC6 CDT1 GMNN ORC1 ORC4 ORC6 | Meier-Gorlin syndrome (OMIM PS224690) | AR (AD) | Patellar aplasia or hypoplasia; microcephaly; genital anomalies; contractures | Severe intrauterine & postnatal growth restriction; bilateral microtia |
| ERCC6 ERCC8 | Cerebrooculofacioskeletal syndrome (severe fetal form of Cockayne syndrome) | AR | Arthrogryposis; microcephaly; severe ID | Progressive neurodegenerative disorder; congenital cataracts & facial dysmorphism |
| FBN2 | Congenital contractural arachnodactyly | AD | Congenital contractures | Marfanoid habitus; aortic root dilatation; arachnodactyly; hypoplastic calf muscles |
| FOXL2 | Blepharophimosis, ptosis, epicanthus inversus syndrome 1 | AD 2 | Blepharophimosis & ptosis | Epicanthus inversus (a fold of skin that runs from the lower lids inwards & upwards) |
| LMX1B | Nail-patella syndrome | AD | Absent patella; renal anomalies; flexion deformities of knees & hips, clubfoot | Proteinuria; open-angle glaucoma; nail changes |
| RECQL4 | RAPADILINO syndrome (OMIM 266280) | AR | Patellar hypoplasia; hearing loss; cleft palate | Irregular pigmentation w/café au lait spots; normal intelligence; palate defects; radial ray defects; GI abnormalities |
| TBX4 | Ischiocoxopodopatellar syndrome (OMIM 147891) | AD | Patellar aplasia or hypoplasia | Absent, delayed, or irregular ossification of the ischiopubic junctions or infraacetabular axe-cut notches |
| ZEB2 | Mowat-Wilson syndrome | AD 3 | Agenesis of the corpus callosum; genital anomalies; ID; congenital heart disease; microcephaly | Seizures; Hirschsprung disease; short stature |
AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
- 1.
Blepharophimosis, ptosis, epicanthus inversus syndrome type II is isolated; type I is associated with premature ovarian insufficiency.
- 2.
Blepharophimosis, ptosis, epicanthus inversus syndrome is usually inherited in an autosomal dominant manner; autosomal recessive inheritance has been reported in one consanguineous family.
- 3.
Mowat-Wilson syndrome is typically the result of a de novo dominant pathogenic variant.
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 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].
Management
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.
Table 5.
Recommended Evaluations Following Initial Diagnosis in Individuals with KAT6B Disorders
| System/Concern | Evaluation | Comment |
| Development | Developmental assessment |
|
| Neurologic | EEG if clinical suspicion of seizures | |
| Assessment of corpus callosum anomalies & other cerebral malformations | Brain MRI | |
| Gastrointestinal/ Feeding | Gastroenterology / nutrition / feeding team evaluation |
|
| Evaluate for anal anomalies. | ||
| If clinical suspicion of malrotation, perform appropriate imaging. 1 | ||
| Cardiovascular | Evaluation by cardiologist for cardiovascular malformation | Include echocardiogram |
| Genitourinary | Evaluate for genital anomalies in both males & females. | |
| Evaluate for hydronephrosis, cysts or other renal anomalies. | Renal ultrasound | |
| Hearing | Assess for hearing loss. | Audiologic evaluation |
| Ocular | Assess lacrimal duct abnormalities, blepharophimosis, optic nerve anomalies, myopia, & amblyopia. | Ophthalmologic evaluation |
| Endocrine | Assess thyroid function. | |
| Musculoskeletal | Evaluation of contractures or malposition of knees/ feet/ankles & upper limbs | Orthopedic evaluation if needed |
| Evaluation of pelvic, spinal, or thoracic anomalies | X-rays could be considered to complement clinical examination. | |
| Respiratory | Evaluate for laryngomalacia. | |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | To incl genetic counseling |
1. Further evidence of utility is required prior to recommending screening of all individuals with KAT6B disorder for small bowel malrotation with a barium enema study.
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.
Table 6.
Treatment of Manifestations in Individuals with KAT6B Disorders
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| DD/ID | See Developmental Delay / Intellectual Disability Management Issues. | |