Whole-Exome-Sequencing Identifies Mutations in Histone Acetyltransferase Gene KAT6B in Individuals with the Say-Barber-Biesecker Variant of Ohdo Syndrome

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• 作者：Jill Clayton-Smith¹ ;   ; ^{jill.clayton-smith@cmft.nhs.uk} ; James O'Sullivan¹ ; Sarah Daly¹ ; Sanjeev Bhaskar¹ ; Ruth Day¹ ; Beverley Anderson¹ ; Anne  ; K. Voss² ;   ; ³ ; Tim Thomas² ; Leslie  ; G. Biesecker⁴ ; Philip Smith¹ ; Alan Fryer⁵ ; Kate  ; E. Chandler¹ ; Bronwyn Kerr¹ ; May Tassabehji¹ ; Sally-Ann Lynch⁶ ; Malgorzata Krajewska-Walasek⁷ ; Shane McKee⁸ ; Janine Smith⁹ ; Elizabeth Sweeney⁵ ; Sahar Mansour¹⁰ ; Shehla Mohammed¹¹ ; Dian Donnai¹ ; Graeme Black¹
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：11 November 2011
• 年：2011
• 卷：89
• 期：5
• 页码：675-681
• 全文大小：537 K

文摘

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.