Testing

Cytogenetic. Karyotyping is clinically available and 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 mutations in KAT6B.

Table 3. Summary of Molecular Genetic Testing Used in KAT6B-Related Disorders

View in own window

Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
KAT6B	Sequence analysis	Sequence variants 2	11/12 3	Clinical
	Deletion / duplication analysis 4	Exonic or whole-gene deletions	Unknown, none reported	Research only 5

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. Campeau et al [2012a], Simpson et al [2012]

4. Testing that identifies 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. See CMA.

5. No laboratories offering clinical testing for this gene are listed in the GeneTests™ Laboratory Directory; clinical confirmation of mutations identified in a research laboratory may be available. See .

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

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 mutations have occurred in the proximal coding region of that exon.

  • If no mutation is found, sequence analysis of the rest of the gene can be performed; if no mutation is found, cytogenetic analysis can be performed.

  • The yield for deletion/ duplication analysis is unknown as such mutations have not been reported as a cause of GPS.

• For individuals with features suggestive of SBBYSS:

  • Sequence analysis of the entire gene should be performed (starting with exon 18); if no mutation is found, cytogenetic analysis can be performed.

  • The yield for deletion/ duplication analysis is unknown as such mutations have not been reported as a cause of SBBYSS.

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

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in KAT6B.

Natural History

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 club feet. 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

Figure 1. Photographs of 11 individuals with a KAT6B mutation

Arrows point to the relative location of an individual’s mutation in the schematic of the last KAT6B exon (exon 18), the distal part of which encodes the activation (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 2012a] and duodenal rupture in another [Sankararaman et al 2012].

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

Genotype-Phenotype Correlations

GPS. Known mutations causing GPS predict protein truncation and cluster in KAT6B exon 18, the last exon. Because mutations 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 mutant alleles produce truncated proteins.

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

Penetrance

KAT6B alleles with truncating mutations 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 less than one in a million individuals. Approximately 20 persons with GPS, and a similar number with SBBYSS, have been described in the literature.

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

• Medical genetics consultation

• 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 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

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

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 mutation. 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 disease-causing mutation 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 mutation 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 mutation include molecular genetic testing of the parent if the KAT6B mutation 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 disease-causing mutation 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 mutation, the risk to the sibs of inheriting the mutation 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 mutation, the risk to other family members is usually not increased.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. 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 mutation.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Biesecker LG. The Ohdo blepharophimosis syndrome: a third case. J Med Genet. 1991;28:131–4. [PMC free article: PMC1016784] [PubMed: 2002485]
2. Brugha R, Kinali M, Aminu K, Bridges N, Holder SE. Genitopatellar syndrome: a further case. Clin Dysmorphol. 2011;20:163–5. [PubMed: 21412151]
3. 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. 2012;90:282–9. [PMC free article: PMC3276659] [PubMed: 22265014]
4. Campeau PM, Lu JT, Dawson BC, Fokkema IF, Robertson SP, Gibbs RA, Lee BH. The KAT6B-related disorders Genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms. Hum Mutat. 2012;33:1520–5. [PubMed: 22715153]
5. Clayton-Smith J, O'Sullivan J, Daly S, Bhaskar S, Day R, Anderson B, Voss AK, Thomas T, Biesecker LG, Smith P, Fryer A, Chandler KE, Kerr B, Tassabehji M, Lynch SA, Krajewska-Walasek M, McKee S, Smith J, Sweeney E, Mansour S, Mohammed S, Donnai D, Black G. Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome. Am J Hum Genet. 2011;89:675–81. [PMC free article: PMC3213399] [PubMed: 22077973]
6. Cormier-Daire V, Chauvet ML, Lyonnet S, Briard ML, Munnich A, Le Merrer M. Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation. Med Genet. 2000;37:520–4.
7. Day R, Beckett B, Donnai D, Fryer A, Heidenblad M, Howard P, Kerr B, Mansour S, Maye U, McKee S, Mohammed S, Sweeney E, Tassabehji M, de Vries BB, Clayton-Smith J. A clinical and genetic study of the Say/Barber/Biesecker/Young-Simpson type of Ohdo syndrome. Clin Genet. 2008;74:434–44. [PubMed: 18798845]
8. Dobyns WB. Absence makes the search grow longer. Am J Hum Genet. 1996;58:7–16. [PMC free article: PMC1914936] [PubMed: 8554070]
9. Doyon Y, Cayrou C, Ullah M, Landry AJ, Côté V, Selleck W, Lane WS, Tan S, Yang XJ, Côté J. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol Cell. 2006;21:51–64. [PubMed: 16387653]
10. Kraft M, Cirstea IC, Voss AK, Thomas T, Goehring I, Sheikh BN, Gordon L, Scott H, Smyth GK, Ahmadian MR, Trautmann U, Zenker M, Tartaglia M, Ekici A, Reis A, Dörr HG, Rauch A, Thiel CT. Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice. J Clin Invest. 2011;121:3479–91. [PMC free article: PMC3163944] [PubMed: 21804188]
11. Mhanni AA, Dawson AJ, Chudley AE. Vertical transmission of the Ohdo blepharophimosis syndrome. Am J Med Genet. 1998;77:144–8. [PubMed: 9605288]
12. Martinez FJ, Lee JH, Lee JE, Blanco S, Nickerson E, Gabriel S, Frye M, Al-Gazali L, Gleeson JG. Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome. J Med Genet. 2012;49:380–5. [PubMed: 22577224]
13. Neri G, Opitz J. Syndromal (and nonsyndromal) forms of male pseudohermaphroditism. Am J Med Genet. 1999;89:201–9. [PubMed: 10727995]
14. Ohdo S, Madokoro H, Sonoda T, Hayakawa K. Mental retardation associated with congenital heart disease, blepharophimosis, blepharoptosis, and hypoplastic teeth. J Med Genet. 1986;23:242–4. [PMC free article: PMC1049635] [PubMed: 3723552]
15. Penttinen M, Koillinen H, Niinikoski H, Mäkitie O, Hietala M. Genitopatellar syndrome in an adolescent female with severe osteoporosis and endocrine abnormalities. Am J Med Genet A. 2009;149A:451–5. [PubMed: 19208376]
16. Rink BD. Arthrogryposis: a review and approach to prenatal diagnosis. Obstet Gynecol Surv. 2011;66:369–77. [PubMed: 21851751]
17. Sankararaman S, Kurepa D, Velayuthan S, Kakkilaya V, Gates T, Ursin S, Chen H. Another case of genitopatellar syndrome: a case report with additional rare coexistences. Clin Dysmorphol. 2012;21:226–8. [PubMed: 22922314]
18. Say B, Barber N. Mental retardation with blepharophimosis. J Med Genet. 1987;24:511. [PMC free article: PMC1050218] [PubMed: 3656379]
19. Simpson JL. Genetics of the female reproductive ducts. Am J Med Genet. 1999;89:224–39. [PubMed: 10727998]
20. Simpson MA, Deshpande C, Dafou D, Vissers LE, Woollard WJ, Holder SE, Gillessen-Kaesbach G, Derks R, White SM, Cohen-Snuijf R, Kant SG, Hoefsloot LH, Reardon W, Brunner HG, Bongers EM, Trembath RC. De novo mutations of the gene encoding the histone acetyltransferase KAT6B cause Genitopatellar syndrome. Am J Hum Genet. 2012;90:290–4. [PMC free article: PMC3276665] [PubMed: 22265017]
21. Tsukahara M, Opitz JM. Dubowitz syndrome: review of 141 cases including 36 previously unreported patients. Am J Med Genet. 1996;63:277–89. [PubMed: 8723121]
22. White SM, Adès LC, Amor D, Liebelt J, Bankier A, Baker E, Wilson M, Savarirayan R. Two further cases of Ohdo syndrome delineate the phenotypic variability of the condition. Clin Dysmorphol. 2003;12:109–13. [PubMed: 12868473]
23. Yang XJ, Ullah M. MOZ and MORF, two large MYSTic HATs in normal and cancer stem cells. Oncogene. 2007;26:5408–19. [PubMed: 17694082]
24. Young ID, Simpson K. Unknown syndrome: abnormal facies, congenital heart defects, hypothyroidism, and severe retardation. J Med Genet. 1987;24:715–6. [PMC free article: PMC1050356] [PubMed: 3430551]

Suggested Reading

1. 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]

Author Notes

Dr. Brendan Lee’s Web site

Dr. Philippe Campeau’s Web site

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

• 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