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.
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: Samir
authors.initials: S
authors.lastname: Zaidi
authors.forename: Murim
authors.initials: M
authors.lastname: Choi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Lijiang
authors.initials: L
authors.lastname: Ma
authors.forename: Jianming
authors.initials: J
authors.lastname: Jiang
authors.forename: John D
authors.initials: JD
authors.lastname: Overton
authors.forename: Angela
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authors.lastname: Romano-Adesman
authors.forename: Robert D
authors.initials: RD
authors.lastname: Bjornson
authors.forename: Roger E
authors.initials: RE
authors.lastname: Breitbart
authors.forename: Kerry K
authors.initials: KK
authors.lastname: Brown
authors.forename: Nicholas J
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authors.forename: Yee Him
authors.initials: YH
authors.lastname: Cheung
authors.forename: John
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authors.lastname: Deanfield
authors.forename: Steve
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authors.lastname: DePalma
authors.forename: Khalid A
authors.initials: KA
authors.lastname: Fakhro
authors.forename: Joseph
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authors.lastname: Glessner
authors.forename: Hakon
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authors.lastname: Hakonarson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Italia
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Kaltman
authors.forename: Juan
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authors.lastname: Kaski
authors.forename: Richard
authors.initials: R
authors.lastname: Kim
authors.forename: Jennie K
authors.initials: JK
authors.lastname: Kline
authors.forename: Teresa
authors.initials: T
authors.lastname: Lee
authors.forename: Jeremy
authors.initials: J
authors.lastname: Leipzig
authors.forename: Alexander
authors.initials: A
authors.lastname: Lopez
authors.forename: Shrikant M
authors.initials: SM
authors.lastname: Mane
authors.forename: Laura E
authors.initials: LE
authors.lastname: Mitchell
authors.forename: Jane W
authors.initials: JW
authors.lastname: Newburger
authors.forename: Michael
authors.initials: M
authors.lastname: Parfenov
authors.forename: Itsik
authors.initials: I
authors.lastname: Pe'er
authors.forename: George
authors.initials: G
authors.lastname: Porter
authors.forename: Amy E
authors.initials: AE
authors.lastname: Roberts
authors.forename: Ravi
authors.initials: R
authors.lastname: Sachidanandam
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.forename: Howard S
authors.initials: HS
authors.lastname: Seiden
authors.forename: Mathew W
authors.initials: MW
authors.lastname: State
authors.forename: Sailakshmi
authors.initials: S
authors.lastname: Subramanian
authors.forename: Irina R
authors.initials: IR
authors.lastname: Tikhonova
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Dorothy
authors.initials: D
authors.lastname: Warburton
authors.forename: Peter S
authors.initials: PS
authors.lastname: White
authors.forename: Ismee A
authors.initials: IA
authors.lastname: Williams
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhao
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Seidman
authors.forename: Martina
authors.initials: M
authors.lastname: Brueckner
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Gelb
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Goldmuntz
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002648:Child; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D004252:DNA Mutational Analysis; D004742:Enhancer Elements, Genetic / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D050437:Genes, Developmental / Q000235:genetics; D006331:Heart Diseases / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008745:Methylation; D009154:Mutation; D016017:Odds Ratio; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D002843:Chromatin; D006657:Histones; D008239:Lysine