Mutations in SRCAP, Encoding SNF2-Related CREBBP Activator Protein, Cause Floating-Harbor Syndrome

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• 作者：Rebecca  ; L. Hood¹ ; ² ; Matthew  ; A. Lines³ ; Sarah  ; M. Nikkel³ ; ⁴ ; Jeremy Schwartzentruber⁵ ; Chandree Beaulieu⁶ ; Mał ; gorzata  ; J.M. Nowaczyk⁷ ; Judith Allanson³ ; Chong  ; Ae Kim⁸ ; Dagmar Wieczorek⁹ ; Jukka  ; S. Moilanen¹⁰ ; Didier Lacombe¹¹ ; Gabriele Gillessen-Kaesbach¹² ; Margo  ; L. Whiteford¹³ ; Caio  ; Robledo  ; D.C. Quaio⁸ ; Israel Gomy⁸ ; Debora  ; R. Bertola⁸ ; Beate Albrecht⁹ ; Konrad Platzer¹² ; George McGillivray¹⁴ ; Ruobing Zou² ; D.  ; Ross McLeod¹⁵ ; Albert  ; E. Chudley¹⁶ ; ¹⁷ ; Bernard  ; N. Chodirker¹⁶ ; ¹⁷ ; Janet Marcadier⁶ ; FORGE Canada Consortium¹⁸ ; Jacek Majewski⁵ ; ¹⁹ ; Dennis  ; E. Bulman² ; ^{dbulman@ohri.ca} ; Susan  ; M. White¹⁴ ; ²⁰ ; Kym  ; M. Boycott³ ; ⁴ ; ⁶ ; ^{kboycott@cheo.on.ca}
• 刊名：The American Journal of Human Genetics
• 出版年：2012
• 出版时间：10 February 2012
• 年：2012
• 卷：90
• 期：2
• 页码：308-313
• 全文大小：440 K

文摘

Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS.