Dataset Information

De novo mutations in histone-modifying genes in congenital heart disease.

ABSTRACT: Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.

SUBMITTER: Zaidi S

PROVIDER: S-EPMC3706629 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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De novo mutations in histone-modifying genes in congenital heart disease.

Zaidi Samir S Choi Murim M Wakimoto Hiroko H Ma Lijiang L Jiang Jianming J Overton John D JD Romano-Adesman Angela A Bjornson Robert D RD Breitbart Roger E RE Brown Kerry K KK Carriero Nicholas J NJ Cheung Yee Him YH Deanfield John J DePalma Steve S Fakhro Khalid A KA Glessner Joseph J Hakonarson Hakon H Italia Michael J MJ Kaltman Jonathan R JR Kaski Juan J Kim Richard R Kline Jennie K JK Lee Teresa T Leipzig Jeremy J Lopez Alexander A Mane Shrikant M SM Mitchell Laura E LE Newburger Jane W JW Parfenov Michael M Pe'er Itsik I Porter George G Roberts Amy E AE Sachidanandam Ravi R Sanders Stephan J SJ Seiden Howard S HS State Mathew W MW Subramanian Sailakshmi S Tikhonova Irina R IR Wang Wei W Warburton Dorothy D White Peter S PS Williams Ismee A IA Zhao Hongyu H Seidman Jonathan G JG Brueckner Martina M Chung Wendy K WK Gelb Bruce D BD Goldmuntz Elizabeth E Seidman Christine E CE Lifton Richard P RP

Nature 20130512 7453

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for da ...[more]

PMID: 23665959

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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 histone-modifying genes in congenital heart disease.

Publications

De novo mutations in histone-modifying genes in congenital heart disease.

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