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

机译：先天性心脏病组蛋白修饰基因的从头突变

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摘要

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 denovo 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.
机译：先天性心脏病（CHD）是最常见的出生缺陷，影响活产的0.8％。许多病例偶尔发生，并损害生殖适应能力，提示从头突变。在这里，我们通过分析父母-后代三重奏的外显子组测序，比较了362名严重CHD病例和264名对照中从头突变的发生率。冠心病病例显示在发育中的心脏中表达的基因中，蛋白质改变的denovo突变显着过量，破坏性突变（提前终止，移码，剪接位点）的比值比为7.5。在严重冠心病的主要类别中，观察到相似的优势比。我们发现与组蛋白3赖氨酸4（H3K4）甲基化或H2BK120泛素化有关的基因的产生，去除或读取涉及的基因中从头突变过多，而H3K4甲基化是必需的。 SMAD2中还有两个从头突变，可调节胚胎左右组织者中的H3K27甲基化。活化（H3K4甲基化）和失活（H3K27甲基化）染色质标记的组合表征了“平衡的”启动子和增强子，它们调节关键发育基因的表达。这些发现暗示了数百个基因的从头突变，这些基因共同构成了严重CHD的大约10％。

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  • 来源
    《Nature》 |2013年第7453期|220-223|共4页
  • 作者

    Samir Zaidi; Murim Choi; Hiroko Wakimoto; Lijiang Ma; Jianming Jiang; John D. Overton; Angela Romano-Adesman; Robert D. Bjomson; Roger E. Breitbart; Kerry K. Brown; Nicholas J. Carriero; Yee Him Cheung; John Deanfield; Steve DePalma; Khalid A. Fakhro; Joseph Glessner; Hakon Hakonarson; Michael J. Italia; Jonathan R. Kaltman; Juan Kaski; Richard Kim; Jennie K. Kline; Teresa Lee; Jeremy Leipzig; Alexander Lopez; Shrikant M. Mane; Laura E. Mitchell; Jane W. Newburger; Michael Parfenov; Itsik Peer; George Porter; Amy E. Roberts; Ravi Sachidanandam; Stephan J. Sanders; Howard S. Seiden; Mathew W. State; Sailakshmi Subramanian; Irina R. Tikhonova; Wei Wang; Dorothy Warburton; Peter S. White; Ismee A. Williams; Hongyu Zhao; Jonathan G. Seidman; Martina Brueckner; Wendy K. Chung; Bruce D. Gelb; Elizabeth Goldmuntz; Christine E. Seidman; Richard P. Lifton;

  • 作者单位

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Howard Hughes Medical Institute, Yale University, Connecticut 06510, USA;

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Howard Hughes Medical Institute, Yale University, Connecticut 06510, USA;

    Department of Genetics,Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA;

    Department of Genetics,Harvard Medical School, Boston, Massachusetts 02115, USA,Howard Hughes Medical Institute, Harvard University, Boston, Massachusetts 02115, USA;

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Yale Center for Mendelian Genomics, New Haven, Connecticut 06510, USA,Yale Center for Genome Analysis, Yale University, New Haven, Connecticut 06511, USA;

    Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, New York 11040, USA;

    Yale Center for Genome Analysis, Yale University, New Haven, Connecticut 06511, USA,Department of Computer Science, Yale University, New Haven, Connecticut 06511, USA.;

    Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts 02115, USA;

    Department of Genetics,Harvard Medical School, Boston, Massachusetts 02115, USA;

    Yale Center for Genome Analysis, Yale University, New Haven, Connecticut 06511, USA,Department of Computer Science, Yale University, New Haven, Connecticut 06511, USA.;

    Department of Biostatistics, Mailman School of Public Health, Columbia University, New York,New York 10032, USA.;

    Department of Cardiology, University College London, Great Ormond Street Hospital, London WC1N 3JH, UK;

    Department of Genetics,Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Howard Hughes Medical Institute, Yale University, Connecticut 06510, USA;

    Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;

    Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA,Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;

    The Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;

    National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Department of Cardiology, University College London, Great Ormond Street Hospital, London WC1N 3JH, UK;

    Section of Cardiothoracic Surgery, University of Southern California Keck School of Medicine, Los Angeles, California 90089, USA;

    Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York 10032, USA;

    Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA;

    The Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Yale Center for Mendelian Genomics, New Haven, Connecticut 06510, USA,Yale Center for Genome Analysis, Yale University, New Haven, Connecticut 06511, USA;

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Yale Center for Mendelian Genomics, New Haven, Connecticut 06510, USA,Yale Center for Genome Analysis, Yale University, New Haven, Connecticut 06511, USA;

    Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, Texas 77030.USA;

    Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts 02115, USA;

    Department of Genetics,Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Computer Science, Columbia University, New York, New York 10032, USA;

    Department of Pediatrics, University of Rochester Medical Center, The School of Medicine and Dentistry.Rochester, New York 14611, USA;

    Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts 02115, USA;

    Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Program on Neurogenetics, Child Study Center,Department of Psychiatry, Yale University, New Haven, Connecticut 06510, USA;

    Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Program on Neurogenetics, Child Study Center,Department of Psychiatry, Yale University, New Haven, Connecticut 06510, USA;

    Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Yale Center for Mendelian Genomics, New Haven, Connecticut 06510, USA,Yale Center for Genome Analysis, Yale University, New Haven, Connecticut 06511, USA;

    The Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA,Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey 07102, USA;

    Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA,Department of Pathology, Columbia University Medical Center, New York, New Jersey 10032, USA;

    Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,The Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA;

    Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA;

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut 06510, USA;

    Department of Genetics,Harvard Medical School, Boston, Massachusetts 02115, USA;

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Department of Pediatrics Yale University School of Medicine, New Haven, Connecticut 06510, USA;

    Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA,Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA;

    Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA,Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA,The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA;

    Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,Division of Cardiology, The Children's Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA;

    Department of Genetics,Harvard Medical School, Boston, Massachusetts 02115, USA,Howard Hughes Medical Institute, Harvard University, Boston, Massachusetts 02115, USA,Cardiovascular Division, Brigham& Women's Hospital, Harvard University, Boston, Massachusetts02115, USA;

    Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06510, USA,Howard Hughes Medical Institute, Yale University, Connecticut 06510, USA,Yale Center for Mendelian Genomics, New Haven, Connecticut 06510, USA,Yale Center for Genome Analysis, Yale University, New Haven, Connecticut 06511, USA,Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut06510, USA;

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