title: Whole-exome-sequencing identifies mutations in histone acetyltransferase gene KAT6B in individuals with the Say-Barber-Biesecker variant of Ohdo syndrome.
abstract: Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance. A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate. The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations. In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced. Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS. Where parental samples were available, the mutations were shown to have occurred de novo. During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds. The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype. This is a further example of how perturbation of a protein involved in chromatin modification might give rise to a multisystem developmental disorder.
authors.affiliation: Genetic Medicine, St. Mary's Hospital, Manchester Academic Health Sciences Centre, School of Biomedicine, University of Manchester, Manchester M13 9WL, UK. jill.clayton-smith@cmft.nhs.uk
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.forename: James
authors.initials: J
authors.lastname: O'Sullivan
authors.forename: Sarah
authors.initials: S
authors.lastname: Daly
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Bhaskar
authors.forename: Ruth
authors.initials: R
authors.lastname: Day
authors.forename: Beverley
authors.initials: B
authors.lastname: Anderson
authors.forename: Anne K
authors.initials: AK
authors.lastname: Voss
authors.forename: Tim
authors.initials: T
authors.lastname: Thomas
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.forename: Philip
authors.initials: P
authors.lastname: Smith
authors.forename: Alan
authors.initials: A
authors.lastname: Fryer
authors.forename: Kate E
authors.initials: KE
authors.lastname: Chandler
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Kerr
authors.forename: May
authors.initials: M
authors.lastname: Tassabehji
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Lynch
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Krajewska-Walasek
authors.forename: Shane
authors.initials: S
authors.lastname: McKee
authors.forename: Janine
authors.initials: J
authors.lastname: Smith
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sweeney
authors.forename: Sahar
authors.initials: S
authors.lastname: Mansour
authors.forename: Shehla
authors.initials: S
authors.lastname: Mohammed
authors.forename: Dian
authors.initials: D
authors.lastname: Donnai
authors.forename: Graeme
authors.initials: G
authors.lastname: Black
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000328:Adult; D000818:Animals; D016569:Blepharophimosis / Q000235:genetics; D002648:Child; D002843:Chromatin / Q000378:metabolism; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics*; D003409:Congenital Hypothyroidism / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D019066:Facies; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006330:Heart Defects, Congenital; D051548:Histone Acetyltransferases / Q000172:deficiency / Q000235:genetics; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D008607:Intellectual Disability / Q000235:genetics*; D007593:Joint Instability; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: D002843:Chromatin; D018389:Codon, Nonsense; D051548:Histone Acetyltransferases; C487137:KAT6B protein, human
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