Publication Date:
2013-05-15
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706629/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706629/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zaidi, Samir -- Choi, Murim -- Wakimoto, Hiroko -- Ma, Lijiang -- Jiang, Jianming -- Overton, John D -- Romano-Adesman, Angela -- Bjornson, Robert D -- Breitbart, Roger E -- Brown, Kerry K -- Carriero, Nicholas J -- Cheung, Yee Him -- Deanfield, John -- DePalma, Steve -- Fakhro, Khalid A -- Glessner, Joseph -- Hakonarson, Hakon -- Italia, Michael J -- Kaltman, Jonathan R -- Kaski, Juan -- Kim, Richard -- Kline, Jennie K -- Lee, Teresa -- Leipzig, Jeremy -- Lopez, Alexander -- Mane, Shrikant M -- Mitchell, Laura E -- Newburger, Jane W -- Parfenov, Michael -- Pe'er, Itsik -- Porter, George -- Roberts, Amy E -- Sachidanandam, Ravi -- Sanders, Stephan J -- Seiden, Howard S -- State, Mathew W -- Subramanian, Sailakshmi -- Tikhonova, Irina R -- Wang, Wei -- Warburton, Dorothy -- White, Peter S -- Williams, Ismee A -- Zhao, Hongyu -- Seidman, Jonathan G -- Brueckner, Martina -- Chung, Wendy K -- Gelb, Bruce D -- Goldmuntz, Elizabeth -- Seidman, Christine E -- Lifton, Richard P -- 5U54HG006504/HG/NHGRI NIH HHS/ -- F30 HL123238/HL/NHLBI NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- T32 GM007205/GM/NIGMS NIH HHS/ -- U01 HG006546/HG/NHGRI NIH HHS/ -- U01 HL098123/HL/NHLBI NIH HHS/ -- U01 HL098147/HL/NHLBI NIH HHS/ -- U01 HL098153/HL/NHLBI NIH HHS/ -- U01 HL098162/HL/NHLBI NIH HHS/ -- U01 HL098163/HL/NHLBI NIH HHS/ -- U01-HL098123/HL/NHLBI NIH HHS/ -- U01-HL098147/HL/NHLBI NIH HHS/ -- U01-HL098153/HL/NHLBI NIH HHS/ -- U01-HL098162/HL/NHLBI NIH HHS/ -- U01-HL098163/HL/NHLBI NIH HHS/ -- U01-HL098188/HL/NHLBI NIH HHS/ -- U54 HG006504/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jun 13;498(7453):220-3. doi: 10.1038/nature12141. Epub 2013 May 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23665959" target="_blank"〉PubMed〈/a〉
Keywords:
Adult
;
Case-Control Studies
;
Child
;
Chromatin/chemistry/metabolism
;
DNA Mutational Analysis
;
Enhancer Elements, Genetic/genetics
;
Exome/genetics
;
Female
;
Genes, Developmental/genetics
;
Heart Diseases/*congenital/*genetics/metabolism
;
Histones/chemistry/*metabolism
;
Humans
;
Lysine/chemistry/metabolism
;
Male
;
Methylation
;
Mutation
;
Odds Ratio
;
Promoter Regions, Genetic/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
