@article{5926b1d2b9de44109f134ec648e88115,
title = "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.",
author = "Samir Zaidi and Murim Choi and Hiroko Wakimoto and Lijiang Ma and Jianming Jiang and Overton, {John D.} and Angela Romano-Adesman and Bjornson, {Robert D.} and Breitbart, {Roger E.} and Brown, {Kerry K.} and Carriero, {Nicholas J.} and Cheung, {Yee Him} and John Deanfield and Steve Depalma and Fakhro, {Khalid A.} and Joseph Glessner and Hakon Hakonarson and Italia, {Michael J.} and Kaltman, {Jonathan R.} and Juan Kaski and Richard Kim and Kline, {Jennie K.} and Teresa Lee and Jeremy Leipzig and Alexander Lopez and Mane, {Shrikant M.} and Mitchell, {Laura E.} and Newburger, {Jane W.} and Michael Parfenov and Itsik Pe'Er and George Porter and Roberts, {Amy E.} and Ravi Sachidanandam and Sanders, {Stephan J.} and Seiden, {Howard S.} and State, {Mathew W.} and Sailakshmi Subramanian and Tikhonova, {Irina R.} and Wei Wang and Dorothy Warburton and White, {Peter S.} and Williams, {Ismee A.} and Hongyu Zhao and Seidman, {Jonathan G.} and Martina Brueckner and Chung, {Wendy K.} and Gelb, {Bruce D.} and Elizabeth Goldmuntz and Seidman, {Christine E.} and Lifton, {Richard P.}",
note = "Funding Information: Acknowledgements The authors are grateful to the patients and families who participated inthisresearch.Wethank thefollowingteammembers for contributions to patient recruitment: D. Awad, K. Celia, D. Etwaru, R. Korsin, A. Lanz, E. Marquez, J. K. Sond, A. Wilpers, R. Yee (Columbia Medical School); K. Boardman, J. Geva, J. Gorham, B. McDonough, A. Monafo, J. Stryker (Harvard Medical School); N. Cross (Yale School of Medicine); S. M. Edman, J. L. Garbarini, J. E. Tusi, S. H. Woyciechowski (Children{\textquoteright}s Hospital of Philadelphia); J. Ellashek and N. Tran (Children{\textquoteright}s Hospital of Los Angeles); K. Flack (University College London); D.Gruber, N. Stellato (Steve and Alexandra Cohen Children{\textquoteright}s Medical Center of New York); D. Guevara, A. Julian, M. Mac Neal, C. Mintz (Icahn School of Medicine at Mount Sinai); and E. Taillie (University of Rochester School of Medicine and Dentistry). We also thank V. Spotlow, P. Candrea, K. Pavlik and M. Sotiropoulosfor their expert production of exome sequences.We thank B. Bernstein and R. Ryan (Massachusetts General Hospital) and B. Bruneau (Gladstone Institute and University of California, San Francisco) for discussions. This work was supported by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI) Pediatric Cardiac Genomics Consortium (U01-HL098188, U01-HL098147, U01-HL098153, U01-HL098163, U01-HL098123, U01-HL098162) and in part by the Simons Foundation for Autism Research and the NIH Centers for Mendelian Genomics (5U54HG006504).",
year = "2013",
doi = "10.1038/nature12141",
language = "English",
volume = "498",
pages = "220--223",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7453",
}