KAT6B-Related Disorders via the KAT6B Gene
Summary and Pricing 
Test Method
Sequencing and CNV Detection via NextGen Sequencing using PG-Select Capture Probes
| Test Code | Test Copy Genes | Test CPT Code | Gene CPT Codes Copy CPT Code | Base Price | |
|---|---|---|---|---|---|
| 3125 | KAT6B | 81479 | 81479,81479 | $990 | Order Options and Pricing |
Pricing Comments
Testing run on PG-select capture probes includes CNV analysis for the gene(s) on the panel but does not permit the optional add on of exome-wide CNV analysis. Any of the NGS platforms allow reflex to other clinically relevant genes, up to whole exome or whole genome sequencing depending upon the base platform selected for the initial test.
An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.
This test is also offered via a custom panel (click here) on our exome or genome backbone which permits the optional add on of exome-wide CNV or genome-wide SV analysis.
Turnaround Time
3 weeks on average for standard orders or 2 weeks on average for STAT orders.
Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.
Targeted Testing
For ordering sequencing of targeted known variants, go to our Targeted Variants page.
Clinical Features and Genetics
Clinical Features
Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and genitopatellar syndrome (GPS) are rare disorders with several overlapping clinical features. Symptoms common to both syndromes include developmental delay; congenital hearts defects; hearing loss; skeletal deformities; and dental, thyroid, and genital anomalies (Campeau et al. 2012). SBBYSS can be distinguished by characteristic dysmorphic features that include blepharophimosis, bulbous nasal tip, small mouth, a thin upper lip and immobile mask-like face; long thumbs and great toes; and lacrimal duct anomalies. Genital anomaly, in the form of cryptorchidism, is present in males only. Symptoms at onset include hypotonia and feeding difficulties; and appear usually in infancy (Ohdo et al. 1986; Say and Barber 1987; Biesecker, 1991; Clayton-Smith et al. 2011). The hallmark features of GPS include hypoplasia or agenesis of the patellae; flexion deformities of the hips and knees and club feet; kidneys anomalies in the form of renal cysts and hydronephrosis; and agenesis of the corpus callosum with microcephaly. Genital anomalies are present in both males and females. Additional features include facial dysmorphism; brachydactyly; and pulmonary hypoplasia. Symptoms begin usually in infancy, although prenatal onset has been reported (Cormier-Daire et al. 2000; Reardon et al. 2002; Penttinen et al. 2009) Noonan Syndrome (NS) is characterized by dysmorphic facial features, growth and congenital heart defects, and musculoskeletal abnormalities. Cardiac abnormalities are found in up to 80% of patients and include pulmonary valve stenosis, atrial septal defect, atrioventricular canal defect, and hypertrophic cardiomyopathy. Musculoskeletal abnormalities include short stature, chest deformity with sunken or raised sternum, and short webbed neck. Several additional abnormalities have been described and include renal, genital, hematological, neurologic, cognitive, behavioral, gastrointestinal, dental, and lymphatic findings. Intelligence is usually normal; however, learning disabilities may be present. NS is characterized by extensive clinical heterogeneity, even among members of the same family. Diagnosis is often made in infancy or early childhood. Symptoms often change and lessen with advancing age. The prevalence of NS is estimated at 1 in 1000 to 1 in 2,500 births worldwide (Allanson et al. 1985; Romano et al. 2010; Smpokou et al. 2012).
Genetics
Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and genitopatellar syndrome (GPS) are both caused by heterozygous pathogenic variants in the KAT6B gene (Clayton-Smith et al. 2011; Campeau et al AJHG. 2012; Simpson et al. 2012; Soden et al. 2014). Variants are all truncating and include nonsense, small deletions and insertions, and indels. All variants occurred de novo. About 10 GPS-causative variants have been reported to date. They are all clustered in the proximal part of the last exon and lead to a truncated protein lacking the activating domain. Twelve variants were reported in patients with SBBYSS. The majority are distributed throughout the entire length of the gene and lead to nonsense-mediated decay. A few variants occured more distally in the last exon (Campeau et al. 2012). Defects in the KAT6B gene appear to be a rare cause of Noonan syndrome. To date, only one patient with a Noonan-like syndrome phenotype was reported to have a de novo balanced translocation in KAT6B. Clinical features in the latter patient overlap with those of Noonan syndrome and included short stature; distinct facial features with blepharophimosis, ptosis, high arched eyebrows, low-set ears with overfolded helix and fleshy lobe, smooth philtrum, retrognathia, and a high arched palate; and attention deficit, hyperactivity disorder, and learning disability (Kraft et al. 2011). At least 70% of patients with a diagnosis of Noonan syndrome have heterozygous germline pathogenic variants in twelve genes (Romano et al. 2010; Tartaglia et al. 2010; Aoki et al. 2013). Ten of these genes (PTPN11, SOS1, RAF1, KRAS, HRAS, SHOC2, BRAF, NRAS, MAP2K1 and MAP2K1) encode components of the main Ras/MAPK signaling pathway; while CBL and RIT1 encode proteins that are involved in its regulation (Rauen 2013; Martinelli et al. 2010; Niemeyer et al. 2010; Kraft et al. 2011; Aoki et al. 2013). The KAT6B gene, also known as MYST4, encodes one of five members of the MYST histone acetyltransferase (MYST HAT) family that is involved in histone acetylation, which is a characteristic of actively transcribed genes (MacDonald et al. 2009).
Clinical Sensitivity - Sequencing with CNV PG-Select
Pathogenic variants in KAT6B were identified in all patients with a typical clinical presentation of SBBYSS (Clayton-Smith et al. 2011) and in over 60% of patients with a clinical diagnosis of GPS (Simpson et al. 2012).
Testing Strategy
This test provides full coverage of all coding exons of the KAT6B gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.
Indications for Test
Patients with clinical features of SBBYSS or GPS and their family members are candidates for this test. Patients with clinical features suggestive of Noonan syndrome and no pathogenic variants in the PTPN11, SOS1, RAF1, KRAS, HRAS, SHOC2, BRAF, NRAS, MAP2K1, MAP2K1,CBL or RIT1 genes are also candidates for this test.
Patients with clinical features of SBBYSS or GPS and their family members are candidates for this test. Patients with clinical features suggestive of Noonan syndrome and no pathogenic variants in the PTPN11, SOS1, RAF1, KRAS, HRAS, SHOC2, BRAF, NRAS, MAP2K1, MAP2K1,CBL or RIT1 genes are also candidates for this test.
Gene
| Official Gene Symbol | OMIM ID |
|---|---|
| KAT6B | 605880 |
| Inheritance | Abbreviation |
|---|---|
| Autosomal Dominant | AD |
| Autosomal Recessive | AR |
| X-Linked | XL |
| Mitochondrial | MT |
Diseases
| Name | Inheritance | OMIM ID |
|---|---|---|
| Genitopatellar Syndrome | AD | 606170 |
| Young Simpson Syndrome | AD | 603736 |
Citations
- Allanson JE, Hall JG, Hughes HE, Preus M, Witt RD. 1985. Noonan syndrome: the changing phenotype. Am. J. Med. Genet. 21: 507-514. PubMed ID: 4025385
- Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, Ogata T, Takada F, Yano M, Ando T, Hoshika T, Barnett C, Ohashi H, Kawame H, Hasegawa T, Okutani T, Nagashima T, Hasegawa S, Funayama R, Nagashima T, Nakayama K, Inoue S, Watanabe Y, Ogura T, Matsubara Y. 2013. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am. J. Hum. Genet. 93:173-180.
PubMed ID: 23791108 - Biesecker LG. 1991. The Ohdo blepharophimosis syndrome: a third case. J. Med. Genet. 28: 131–134. PubMed ID: 2002485
- Campeau PM, Kim JC, Lu JT, Schwartzentruber JA, Abdul-Rahman OA, Schlaubitz S, Murdock DM, Jiang M-M, 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. 2012. Mutations in KAT6B, Encoding a Histone Acetyltransferase, Cause Genitopatellar Syndrome. Am J Hum Genet 90: 282–289. PubMed ID: 22265014
- Campeau PM, Lu JT, Dawson BC, Fokkema IFAC, Robertson SP, Gibbs RA, Lee BH. 2012. The KAT6B-related disorders Genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms. Hum Mutat 33: 1520–1525. PubMed ID: 22715153
- 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. 2011. 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 89: 675–681. PubMed ID: 22077973
- Cormier-Daire V, Chauvet M-L, Lyonnet S, Briard M-L, Munnich A, Merrer ML. 2000. Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation. J Med Genet 37: 520–524. PubMed ID: 10882755
- 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. 2011. Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome–like phenotype and hyperactivated MAPK signaling in humans and mice. Journal of Clinical Investigation 121: 3479–3491. PubMed ID: 21804188
- MacDonald VE, Howe LJ. 2009. Histone acetylation: where to go and how to get there. Epigenetics 4: 139–143. PubMed ID: 19430203
- Martinelli S, Luca A De, Stellacci E, Rossi C, Checquolo S, Lepri F, Caputo V, Silvano M, Buscherini F, Consoli F, Ferrara G, Digilio MC, Cavaliere ML, van Hagen JM, Zampino G, van der Burgt I, Ferrero GB, Mazzanti L, Screpanti I, Yntema HG, Nillesen WM, Savarirayan R, Zenker M, Dallapiccola B, Gelb BD, Tartaglia M. 2010. Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype. Am J Hum Genet 87: 250–257. PubMed ID: 20619386
- Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, Bunda S, Finklestein JZ, Sakamoto KM, Gorr TA, Mehta P, Schmid I, Kropshofer G, Corbacioglu S, Lang PJ, Klein C, Schlegel PG, Heinzmann A, Schneider M, Starý J, van den Heuvel-Eibrink MM, Hasle H, Locatelli F, Sakai D, Archambeault S, Chen L, Russell RC, Sybingco SS, Ohh M, Braun BS, Flotho C, Loh ML. 2010. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nature Genetics 42: 794–800. PubMed ID: 20694012
- Ohdo S, Madokoro H, Sonoda T, Hayakawa K. 1986. Mental retardation associated with congenital heart disease, blepharophimosis, blepharoptosis, and hypoplastic teeth. J Med Genet 23: 242–244. PubMed ID: 3723552
- Penttinen M, Koillinen H, Niinikoski H, Mäkitie O, Hietala M. 2009. Genitopatellar syndrome in an adolescent female with severe osteoporosis and endocrine abnormalities. Am. J. Med. Genet. A 149A: 451–455. PubMed ID: 19208376
- Rauen KA. 2013. The RASopathies. Annu Rev Genomics Hum Genet 14: 355–369. PubMed ID: 23875798
- Reardon W. 2002. Genitopatellar syndrome: a recognizable phenotype. Am. J. Med. Genet. 111: 313–315. PubMed ID: 12210329
- Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. 2010. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 126: 746-759. PubMed ID: 20876176
- Say B, Barber N. 1987. Mental retardation with blepharophimosis. J Med Genet 24: 511. PubMed ID: 3656379
- Simpson MA, Deshpande C, Dafou D, Vissers LELM, 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. 2012. De Novo Mutations of the Gene Encoding the Histone Acetyltransferase KAT6B Cause Genitopatellar Syndrome. Am J Hum Genet 90: 290–294. PubMed ID: 22265017
- Smpokou P, Tworog-Dube E, Kucherlapati RS, Roberts AE. 2012. Medical complications, clinical findings, and educational outcomes in adults with Noonan syndrome. American Journal of Medical Genetics Part A 158A: 3106–3111. PubMed ID: 23165751
- Soden SE, Saunders CJ, Willig LK, Farrow EG, Smith LD, Petrikin JE, LePichon J-B, Miller NA, Thiffault I, Dinwiddie DL, Twist G, Noll A, Heese BA, Zellmer L, Atherton AM, Abdelmoity AT, Safina N, Nyp SS, Zuccarelli B, Larson IA, Modrcin A, Herd S, Creed M, Ye Z, Yuan X, Brodsky RA, Kingsmore SF. 2014. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med 6: 265ra168. PubMed ID: 25473036
- Tartaglia M, Zampino G, Gelb BD. 2010. Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis. Mol Syndromol 1: 2–26. PubMed ID: 20648242
Ordering/Specimens
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