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De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.

ABSTRACT: Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.

SUBMITTER: Homsy J 

PROVIDER: S-EPMC4890146 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.

Homsy Jason J   Zaidi Samir S   Shen Yufeng Y   Ware James S JS   Samocha Kaitlin E KE   Karczewski Konrad J KJ   Karczewski Konrad J KJ   DePalma Steven R SR   McKean David D   Wakimoto Hiroko H   Gorham Josh J   Jin Sheng Chih SC   Deanfield John J   Giardini Alessandro A   Porter George A GA   Kim Richard R   Bilguvar Kaya K   López-Giráldez Francesc F   Tikhonova Irina I   Mane Shrikant S   Romano-Adesman Angela A   Qi Hongjian H   Vardarajan Badri B   Ma Lijiang L   Daly Mark M   Roberts Amy E AE   Russell Mark W MW   Mital Seema S   Newburger Jane W JW   Gaynor J William JW   Breitbart Roger E RE   Iossifov Ivan I   Ronemus Michael M   Sanders Stephan J SJ   Kaltman Jonathan R JR   Seidman Jonathan G JG   Brueckner Martina M   Gelb Bruce D BD   Goldmuntz Elizabeth E   Lifton Richard P RP   Seidman Christine E CE   Chung Wendy K WK  

Science (New York, N.Y.) 20151201 6265

Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morph  ...[more]

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