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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]

PMID: 26785492

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Project description:BackgroundDe novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.MethodsWe studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).ResultsTwo hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (P=5.63×10-12). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; P=5.33×10-04) and longer times to final extubation (hazard ratio, 0.74; P=0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (P=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P=0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; P=1.61×10-05) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation.ConclusionsIn patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

Dataset Information

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

Publications

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

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