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KAT6B-Related Disorders

, MD, FRCPC and , MD, PhD.

Author Information

Initial Posting: ; Last Revision: January 10, 2013.

Summary

Clinical characteristics.

KAT6B-related disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker variant of Ohdo syndrome (Ohdo syndrome, SBBYS variant, or SBBYSS [Say-Barber-Biesecker-Young-Simpson syndrome]). Both phenotypes are characterized by significant global developmental delay/intellectual disability, hypotonia, genital abnormalities in males (cryptorchidism), and patellar hypoplasia/agenesis. Congenital heart defects, dental anomalies, hearing loss, and thyroid anomalies are common to both phenotypes. Also observed in GPS are flexion contractures of the hips and knees, clubfoot, agenesis of the corpus callosum with microcephaly, and hydronephrosis and/or multiple renal cysts. In SBBYS lower extremity joint stiffness, long thumbs/great toes, immobile mask-like face, blepharophimosis/ptosis, and lacrimal duct anomalies are observed.

Diagnosis/testing.

The diagnosis of KAT6B-related disorders is based on clinical findings consistent with the GPS-SBBYSS group of disorders and presence of a heterozygous pathogenic variant in KAT6B.

Management.

Treatment of manifestations: Educational intervention and speech therapy beginning in infancy. Orthopedic intervention as needed for contractures and clubfoot and physical therapy to help increase joint mobility. Routine management of cryptorchidism, congenital heart defects, dental anomalies, hearing loss, thyroid anomalies, and ophthalmologic findings.

Surveillance: Yearly evaluations of developmental progress, contractures and/or scoliosis by an orthopedist, ophthalmologic problems such as amblyopia (in SBBYSS), thyroid function tests, heart defects, and kidneys if hydronephrosis and/or multiple renal cysts are present

Genetic counseling.

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

GeneReview Scope

KAT6B-Related Disorders: Included Phenotypes 1
  • Genitopatellar syndrome
  • Say-Barber-Biesecker variant of Ohdo syndrome

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotyheps see Differential Diagnosis.

Diagnosis

KAT6B-related disorders include genitopatellar syndrome (GPS) and Say-Barber-Biesecker variant of Ohdo syndrome (SBBYSS [Say-Barber-Biesecker-Young-Simpson syndrome]), which can also be referred to as the GPS-SBBYSS group of disorders.

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

Table 1.

Indicative Guide for Testing for GPS

CategoryFeatures
Major features
  • Genital anomalies (females: clitoromegaly and/or hypoplasia of the labia minora or majora; males: cryptorchidism and scrotal hypoplasia)
  • Patellar hypoplasia/agenesis
  • Flexion contractures at the hips and knees (including clubfoot)
  • Agenesis of the corpus callosum with microcephaly
  • Hydronephrosis and/or multiple renal cysts
Minor features
  • Congenital heart defect
  • Dental anomalies (delayed eruption of teeth)
  • Hearing loss
  • Thyroid anomalies
  • Anal anomalies
  • Hypotonia
  • Global developmental delay/intellectual disability

Say-Barber-Biesecker variant of Ohdo syndrome (SBBYSS). Criteria for the clinical diagnosis of SBBYSS proposed by White et al [2003] included the mandatory findings of blepharophimosis, ptosis, and intellectual disability and the supporting findings of depressed nasal bridge, hypoplastic teeth, deafness, undescended testes, and hypotonia. The authors propose slightly broader features (Table 2) to prompt KAT6B molecular genetic testing in individuals suspected of having SBBYSS. Individuals with two major features or one major feature and two minor features are likely to have a KAT6B pathogenic variant.

Table 2.

Indicative Guide for Testing for Ohdo/SBBYS Syndrome (SBBYSS)

CategoryFeatures
Major features
  • Long thumbs/great toes
  • Immobile mask-like face
  • Blepharophimosis/ptosis
  • Lacrimal duct anomalies
  • Patellar hypoplasia/agenesis
Minor features
  • Congenital heart defect
  • Dental anomalies (hypoplastic teeth and/or delayed eruption of teeth)
  • Hearing loss
  • Thyroid anomalies
  • Cleft palate
  • Genital anomalies (males: cryptorchidism)
  • Hypotonia
  • Global developmental delay/intellectual disability

Testing

Cytogenetic. Karyotyping may be useful; one individual had a “Noonan syndrome-like” phenotype resulting from a translocation interrupting intron 3 of KAT6B [Kraft et al 2011].

Molecular Genetic Testing

Gene. KAT6B-related disorders are caused by mutation of KAT6B.

Table 3.

Summary of Molecular Genetic Testing Used in KAT6B-Related Disorders

Gene 1Test MethodVariants Detected 2Variant Detection Frequency by Test Method 3
KAT6BSequence analysis 4Sequence variants11/12 5
Deletion/duplication analysis 6Exon or whole-gene deletionsUnknown, none reported
1.
2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a variant that is present in the indicated gene

4.

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.

5.
6.

Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • For individuals with features suggestive of GPS:
    • Sequence analysis is appropriate, with particular focus on KAT6B exon 18 because all known GPS-causing pathogenic variants have occurred in the proximal coding region of that exon.
    • If no pathogenic variant is found, sequence analysis of the rest of the gene can be performed; if no pathogenic variant is found, cytogenetic analysis can be performed.
    • The yield for deletion/ duplication analysis is unknown as such variants have not been reported as a cause of GPS.
  • For individuals with features suggestive of SBBYSS:

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Characteristics

Clinical Description

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.

Most of the musculoskeletal findings in GPS involve the lower extremities: flexion contractures of the hips and knees and clubfoot. These can significantly hinder mobility, especially since the knees in some cases cannot be extended beyond 90 degrees.

Spinal, costal, and pelvic anomalies are distributed with approximately equal frequency in affected individuals (i.e., ~33% manifest each of the following):

  • Spinal anomalies are thoracolumbar kyphoscoliosis.
  • Costal anomalies include the presence of small cervical ribs, a narrow thorax and one absent pair of ribs. Clavicular exostoses have also been noted.
  • Pelvic anomalies on radiographies include hip dislocations and hypoplasia of the iliac bone, ischia, and pubic rami. Limited hip extension can significantly impair mobility.

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 intellectual disability are noted in all individuals diagnosed to date. The delay is global (motor and intellectual) and usually severe. Few descriptions of the development in older children exist; some can communicate through vocalization, manipulate objects, and ambulate with walkers or tricycles.

Some have hypotonia at birth, resulting in respiratory and feeding difficulties which can require invasive procedures (see Management). 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.

Anal anomalies. Anal anomalies such as anal atresia or stenosis, rectal duplication, and an anteriorly positioned anus are occasionally seen in GPS.

Genital anomalies. Most females have clitoromegaly and/or hypoplasia of the labia (minora or majora). Males often have cryptorchidism and scrotal hypoplasia. One female age 14 years who lacked any sign of puberty was described as having either delayed puberty or hypogonadotropic hypogonadism [Penttinen et al 2009].

Renal anomalies. Hydronephrosis is seen in a majority of persons with GPS; multiple renal cysts are seen in a minority. These are not known to lead to end-stage renal disease.

Heart defects. Congenital heart defects are noted in about 50% of affected individuals. The most frequent defects are atrial septal defects, ventricular septal defects, and patent foramen ovale.

Facial features. Individuals with GPS can have:

  • Prominent cheeks
  • Nose with either a bulbous end or a broad or prominent base
  • Micro/retrognathia or prognathism
  • Bitemporal narrowing
  • Prominent eyes

See Figure 1.

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 (more...)

Other features

  • Some children with GPS have hypotonia and/or laryngomalacia, which can exacerbate the feeding difficulties and respiratory difficulties present in some infants.
  • A minority of patients have delayed eruption of normal teeth, hypothyroidism, and mild to severe bilateral non-progressive sensorineural hearing loss.
  • Small bowel malrotation was seen in two affected individuals [Brugha et al 2011, Campeau et al 2012b] and duodenal rupture in another [Sankararaman et al 2012].

Other rarer features present in GPS are discussed in Campeau et al [2012b] and Penttinen et al [2009].

SBBYSS

Skeletal features. Most individuals have long thumbs and great toes. Some have patellar anomalies similar to those seen in GPS (i.e. aplasia or hypoplasia). Pectus chest deformity is seen in some. In one study, most patients had joint hypermobility in the upper extremities and large-joint stiffness in the lower extremities, sometimes to the point of contractures [Day et al 2008]. If not corrected, contractures can limit mobility.

Neurologic features. Patients have intellectual disability and severe, global developmental delay. In a study by Day et al [2008], children sat at 18 months and walked at 3.5 years. Fine motor skills and coordination were impaired. A minority were toilet trained and all required help dressing. A few children spoke at age 4.5 years, eventually making short sentences; receptive language was better than expressive language. Others communicated by vocalization only.

Some neonates have hypotonia, with feeding and respiratory difficulties requiring hospitalization.

Many have a smaller than average OFC but not frank microcephaly.

Genital anomalies. Cryptorchidism is seen in males. Females do not have genital anomalies. Pubertal delays are not seen.

Cardiac defects. Congenital heart defects are noted in about 50%. The most frequent defects are atrial septal defects, ventricular septal defects, and patent foramen ovale.

Facial features. Facial appearance is distinctive with a mask-like facies, blepharophimosis, and ptosis. Some have prominent cheeks, and a nose with either a bulbous end or a broad or prominent base. See Figure 1.

Other features

  • Feeding difficulties are seen. Contributing factors may be hypotonia and cleft palate, seen in one third of affected individuals [Clayton-Smith et al 2011].
  • Myopia and amblyopia are common. Some have lacrimal duct abnormalities.
  • Dental anomalies include natal teeth, retained primary dentition, and delayed eruption of teeth. Teeth can be misshapen or discolored.
  • A minority of patients have hypothyroidism, some of them having thyroid agenesis or hypoplasia.
  • Hearing loss, both conductive and sensorineural is often present.

Rarer features present in SBBYSS are discussed in [Day et al 2008].

Genotype-Phenotype Correlations

GPS. Known pathogenic variants causing GPS predict protein truncation and cluster in KAT6B exon 18, the last exon. Because pathogenic variants that predict truncation (nonsense, frameshift) that occur in the final exon of a gene typically do not result in nonsense-mediated decay of the mRNA, it is predicted that these KAT6B mutated alleles produce truncated proteins.

SBBYSS. Known pathogenic variants causing SBBYSS occur mostly in exon 18 but some individuals – often with an atypical SBBYSS phenotype – were found to have pathogenic variants elsewhere in the gene. Nonsense/frameshift variants in exons other than 18 are predicted to lead to nonsense-mediated decay and lack of protein expression from that allele. Pathogenic variants in KAT6B exon 18 typically occur more distally than GPS-associated variants (Figure 1).

Penetrance

KAT6B alleles with truncating pathogenic variants have a high penetrance. Truncating variants are not found in polymorphism databases and all family members with truncating variants reported have findings of GPS or SBBYSS [Campeau et al 2012a, Simpson et al 2012].

Nomenclature

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

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

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 chapter.

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

Prevalence

The prevalence of KAT6B-related conditions is not known, but is estimated at fewer than one in a million individuals. Approximately 20 persons with GPS, and a similar number with SBBYSS, have been described in the literature.

Differential Diagnosis

A minority of children clinically diagnosed as GPS or SBBYSS do not have pathogenic variants in KAT6B [Clayton-Smith et al 2011, Simpson et al 2012].

Other syndromes with patellar anomalies

  • Nail patella syndrome (LMX1B, autosomal dominant). Clinical tetrad of changes in the nails, knees, and elbows, and the presence of iliac horns
  • Small patella syndrome (TBX4, autosomal dominant). Aplasia or hypoplasia of the patellae and absent, delayed, or irregular ossification of the ischiopubic junctions or infraacetabular axe-cut notches
  • RAPADILINO syndrome (RECQL4, autosomal recessive). Irregular pigmentation with café au lait spots, small stature, palate defects, radial ray defects, patellar hypoplasia, and gastrointestinal abnormalities (See Baller-Gerold Syndrome, Genetically Related Disorders.)
  • Meier-Gorlin syndrome (pre-replication complex genes: ORC1, ORC4, ORC6, CDT1, CDC6, autosomal recessive). Severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellae

Other syndromes with blepharophimosis

  • Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) (FOXL2, autosomal dominant). Reduced horizontal diameter of the palpebral fissures, ptosis, and a fold of skin that runs from the lower lids inwards and upwards (epicanthus inversus). Type II is isolated; type I is associated with premature ovarian insufficiency (POI).
  • Dubowitz syndrome (NSUN2 in one family [Martinez et al 2012], autosomal recessive). Blepharophimosis, ptosis, microcephaly, intellectual disability, growth retardation, eczema (features variably present) [Tsukahara & Opitz 1996]
  • Fetal alcohol spectrum disorders (FASD). Classic fetal alcohol syndrome includes in utero alcohol exposure, short palpebral fissures, flat midface, long and smooth philtrum, thin vermilion of the upper lip, pre- and post-natal growth retardation, 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.

Other syndromes with agenesis of the corpus callosum and genital anomalies

  • Mowat-Wilson syndrome (ZEB2, autosomal dominant). Agenesis of the corpus callosum, intellectual disability, microcephaly, seizures, Hirschsprung disease, congenital heart disease, hypospadias, genitourinary anomalies, and short stature
  • X-linked lissencephaly with absent corpus callosum and ambiguous genitalia (ARX)

Other syndromes with agenesis of the corpus callosum and other malformations [Dobyns 1996]

Other syndromes with genital anomalies and multiple congenital anomalies are reviewed in Neri & Opitz [1999], Simpson [1999].

Other syndromes that present with congenital contractures

An approach to diagnosis of these syndromes is discussed elsewhere [Rink 2011].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with KAT6B-related disorders, the following are recommended:

GPS and SBBYSS

  • Consultation with a clinical geneticist and/or genetic counselor
  • Evaluation by developmental specialist
  • Feeding evaluation
  • Baseline hearing evaluation
  • Thyroid function tests

GPS

  • Evaluation of males for cryptorchidism
  • Orthopedic evaluation if contractures are present or feet/ankles are malpositioned
  • Hip radiographs to evaluate for femoral head dislocation
  • Renal ultrasound examination for hydronephrosis and cysts
  • Echocardiogram for congenital heart defects
  • Evaluation for laryngomalacia if respiratory issues are present
  • Evaluation by gastroenterologist as needed, particularly if bowel malrotation is suspected

SBBYSS

  • Ophthalmologic evaluation for lacrimal duct abnormalities, amblyopia, and other issues

Treatment of Manifestations

The following are appropriate:

  • Developmental. Educational intervention and speech therapy beginning in infancy because of the high risk for motor, cognitive, speech, and language delay
  • Skeletal features
    • Referral to an orthopedist for consideration of surgical release of contractures
    • Early referral to physical therapy to help increase joint mobility
  • Genital anomalies. Orchiopexy in males with undescended testes
  • Anal anomalies. Surgery as required
  • Renal anomalies. Referral to an urologist or nephrologist as indicated
  • Heart defects. Routine management
  • Facial features. In SBBYSS, ptosis surgery and cleft palate repair if present
  • Other features
    • Hearing aids as needed for hearing loss
    • Thyroid hormone replacement as needed
    • Intervention for respiratory and feeding issues as needed in the neonatal period
    • Referral to a gastroenterologist for evaluation and treatment of feeding difficulties and bowel malrotation

Surveillance

The following should be assessed annually:

  • Developmental progress
  • Ophthalmologic conditions such as amblyopia (which develops in a majority of patients with SBBYSS)
  • Thyroid function
  • Cardiac function if malformations are present
  • Renal function if hydronephrosis or multiple renal cysts are present
  • Contractures and/or scoliosis

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 www.ClinicalTrialsRegister.eu 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

KAT6B-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • To date, all individuals diagnosed with a KAT6B-related disorder have had a de novo pathogenic variant. Of note, one 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.
  • When the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing of the parent if the KAT6B pathogenic variant has been identified in the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
  • If a parent of the proband has germline mosaicism for a KAT6B pathogenic variant, the risk to the sibs of inheriting the pathogenic variant may be as high as 50%.

Offspring of a proband. To date, individuals with KAT6B-related disorders rarely reproduce. One 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.

Other family members. Because KAT6B-related disorders usually occur as the result of a de novo pathogenic variant, the risk to other family members is usually not increased.

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 clinical evidence of the disorder it is likely that the proband has a de novo pathogenic variant.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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-related disorder.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

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

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for KAT6B-Related Disorders have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

KAT6B-Related Disorders: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
KAT6B10q22​.2Histone acetyltransferase KAT6BKAT6B@LOVD
Lee Lab(KAT6B)
KAT6BKAT6B

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for KAT6B-Related Disorders (View All in OMIM)

603736OHDO SYNDROME, SBBYS VARIANT; SBBYSS
605880LYSINE ACETYLTRANSFERASE 6B; KAT6B
606170GENITOPATELLAR SYNDROME; GTPTS

Gene structure. 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. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Benign coding variants present in at least 1% of the population are in Table 4.

Pathogenic variants. All pathogenic variants known to date are either nonsense or frameshift variants that cause a premature truncation of the protein. All variants were de novo. Variants occurring in more than one individual are shown in Table 4.

  • GPS-causing variants occur in the proximal portion of the last exon (exon 18) (Figure 1) and lead to the expression of a protein without a C-terminal portion (see Normal gene product).
  • SBBYSS-causing variants occur most often in the distal portion of exon 18 (the last exon) or exceptionally in earlier exons, and presumably lead to nonsense-mediated decay and no protein production.

Table 4.

Selected KAT6B Variants

Variant ClassificationDNA Nucleotide ChangePredicted Protein ChangeReference Sequences
Benignc.3649G>Tp.Ala1217Ser
(rs573729861
NM_012330​.3
NP_036462​.2
c.4495G>Ap.Val1499Ile
(rs3740321
c.4835G>Ap.Arg1612His
(rs728034611
Pathogenic - GPSc.3769_3772delTCTAp.Lys1258GlyfsTer13
Pathogenic -SBBYSSc.4205_4206delp.Ser1402CysfsTer5
c.5201_5210dupp.Gln1737HisfsTer41

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Description in dbSNP, a database of single nucleotide polymorphisms (SNPs) and multiple small-scale variations that include insertions/deletions, microsatellites, and non-polymorphic variants

Normal gene product. KAT6B, a ubiquitously expressed histone acetyltransferase, regulates the expression of various genes, and preferentially acetylates lysine 14 of histone H3 in an in vitro assay [Doyon et al 2006]. KAT6B interacts with the proteins RUNX2, BRPF1, ING5, PPAR-alpha, and atrophin-1; however, the precise roles of these proteins in the mechanism of action of KAT6B are not completely understood (reviewed by Yang & Ullah [2007]).

Abnormal gene product. It is possible that haploinsufficiency or loss of a function mediated by the C-terminal region causes the features common to both conditions, whereas gain-of-function activities would explain the features unique to GPS (such as anomalies of the spine, ribs, and pelvis; renal cysts; hydronephrosis; and agenesis of the corpus callosum). Since only some of the binding partners of KAT6B are known, it is difficult to hypothesize which of these are involved in the pathogenesis of KAT6B-related diseases.

References

Literature Cited

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  • Campeau PM, Kim JC, Lu JT, Schwartzentruber JA, Abdul-Rahman OA, Schlaubitz S, Murdock DM, Jiang MM, Lammer EJ, Enns GM, Rhead WJ, Rowland J, Robertson SP, Cormier-Daire V, Bainbridge MN, Yang XJ, Gingras MC, Gibbs RA, Rosenblatt DS, Majewski J, Lee BH. Mutations in KAT6B, encoding a histone acetyltransferase, cause Genitopatellar syndrome. Am J Hum Genet. 2012a;90:282–9. [PMC free article: PMC3276659] [PubMed: 22265014]
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Suggested Reading

  • Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT. LOVD v.2.0: the next generation in gene variant databases. Hum Mutat. 2011;32:557–63. [PubMed: 21520333]

Chapter Notes

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.

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