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

Nature volume 498, pages 220–223 (2013)Cite this article

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Abstract

Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births1. 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 methylation2,3,4. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left–right organizer5. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes ‘poised’ promoters and enhancers, which regulate expression of key developmental genes6. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.

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Figure 1: Enrichment of nonsynonymous de novo mutations in heart-expressed genes.
Figure 2: de novo mutations in the H3K4 and H3K27 methylation pathways.

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Data deposits

Messenger RNA and protein sequences are available in the RefSeq database (http://www.ncbi.nlm.nih.gov/refseq/) under accession numbers listed in Supplementary Table 4; mutation data are available at dbSNP (http://www.ncbi.nlm.nih.gov/snp) under batch accession 1059065.

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Acknowledgements

The authors are grateful to the patients and families who participated in this research. We thank the following team members 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’s Hospital of Philadelphia); J. Ellashek and N. Tran (Children’s Hospital of Los Angeles); K. Flack (University College London); D.Gruber, N. Stellato (Steve and Alexandra Cohen Children’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. Sotiropoulos for 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).

Author information

Author notes

  1. Samir Zaidi and Murim Choi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Samir Zaidi, Murim Choi, John D. Overton, Khalid A. Fakhro, Alexander Lopez, Shrikant M. Mane, Stephan J. Sanders, Mathew W. State, Irina R. Tikhonova, Hongyu Zhao, Martina Brueckner & Richard P. Lifton

  2. Howard Hughes Medical Institute, Yale University, Connecticut, 06510, USA

    Samir Zaidi, Murim Choi, Khalid A. Fakhro & Richard P. Lifton

  3. Department of Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Hiroko Wakimoto, Jianming Jiang, Kerry K. Brown, Steve DePalma, Michael Parfenov, Jonathan G. Seidman & Christine E. Seidman

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

    Lijiang Ma, Teresa Lee, Dorothy Warburton, Ismee A. Williams & Wendy K. Chung

  5. Howard Hughes Medical Institute, Harvard University, Boston, 02115, Massachusetts, USA

    Jianming Jiang & Christine E. Seidman

  6. Yale Center for Mendelian Genomics, New Haven, 06510, Connecticut, USA

    John D. Overton, Alexander Lopez, Shrikant M. Mane, Irina R. Tikhonova & Richard P. Lifton

  7. Yale Center for Genome Analysis, Yale University, New Haven, 06511, Connecticut, USA

    John D. Overton, Robert D. Bjornson, Nicholas J. Carriero, Alexander Lopez, Shrikant M. Mane, Irina R. Tikhonova & Richard P. Lifton

  8. Steven and Alexandra Cohen Children’s Medical Center of New York, New Hyde Park, 11040, New York, USA

    Angela Romano-Adesman

  9. Department of Computer Science, Yale University, New Haven, 06511, Connecticut, USA

    Robert D. Bjornson & Nicholas J. Carriero

  10. Department of Cardiology, Children’s Hospital Boston, Boston, 02115, Massachusetts, USA

    Roger E. Breitbart, Jane W. Newburger & Amy E. Roberts

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

    Yee Him Cheung

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

    John Deanfield & Juan Kaski

  13. Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, 19104, Pennsylvania, USA

    Joseph Glessner & Hakon Hakonarson

  14. Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Hakon Hakonarson, Peter S. White & Elizabeth Goldmuntz

  15. The Center for Biomedical Informatics, The Children’s Hospital of Philadelphia, Philadelphia, 19104, Pennsylvania, USA

    Michael J. Italia, Jeremy Leipzig, Wei Wang & Peter S. White

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

    Jonathan R. Kaltman

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

    Richard Kim

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

    Jennie K. Kline

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

    Laura E. Mitchell

  20. Department of Computer Science, Columbia University, New York, 10032, New York, USA

    Itsik Pe’er

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

    George Porter

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

    Ravi Sachidanandam, Sailakshmi Subramanian & Bruce D. Gelb

  23. Department of Psychiatry, Program on Neurogenetics, Child Study Center, Yale University, New Haven, 06510, Connecticut, USA

    Stephan J. Sanders & Mathew W. State

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

    Howard S. Seiden & Bruce D. Gelb

  25. Department of Computer Science, New Jersey Institute of Technology, Newark, 07102, New Jersey, USA

    Wei Wang

  26. Department of Pathology, Columbia University Medical Center, New York, 10032, New Jersey, USA

    Dorothy Warburton

  27. Department of Biostatistics, Yale School of Public Health, New Haven, 06510, Connecticut, USA

    Hongyu Zhao

  28. Department of Pediatrics Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Martina Brueckner

  29. Department of Medicine, Columbia University Medical Center, New York, 10032, New York, USA

    Wendy K. Chung

  30. The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA

    Bruce D. Gelb

  31. Division of Cardiology, The Children’s Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Elizabeth Goldmuntz

  32. Cardiovascular Division, Brigham & Women’s Hospital, Harvard University, Boston, 02115, Massachusetts, USA

    Christine E. Seidman

  33. Department of Internal Medicine, Yale University School of Medicine, New Haven, 06510, Connecticut, USA

    Richard P. Lifton

Authors
  1. Samir Zaidi
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  2. Murim Choi
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  3. Hiroko Wakimoto
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  4. Lijiang Ma
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Contributions

Study design: M.B., W.K.C., B.D.G., E.G., H.H., J.R.K., R.P.L., L.E.M., J.G.S., C.E.S., D.W., P.S.W.; cohort ascertainment, phenotypic characterization and recruitment: R.E.B., M.B., W.K.C., J.D., B.D.G., E.G., J.K., R.K., T.L., J.W.N., G.P., A.R.-A., H.S.S., C.E.S., I.A.W.; informatics/data management: R.D.B., R.E.B., N.J.C., M.C., S.D., J.G., H.H., M.J.I., J.L., A.L., S.M.M., J.D.O., M.P., A.E.R., J.G.S., W.W., P.S.W., S.Z.; exome sequencing production: J.D.O., A.L., R.P.L., S.M.M., M.W.S., I.R.T.; de novo mutation validation: W.K.C., L.M.; exome sequencing analysis: K.K.B., Y.H.C., M.C., S.D., K.A.F., J.G., J.K.K., R.P.L., I.P., R.S., S.J.S., J.G.S., C.E.S., S.S., W.W., S.Z.; RNA sequence production/analysis: J.J., M.P., C.E.S., J.G.S., H.W.; statistical analysis: M.C., R.P.L., I.P., A.E.R., C.E.S., J.G.S., S.Z., H.Z.; writing of manuscript: M.B., M.C., W.K.C., B.D.G., E.G., J.R.K., R.P.L., C.E.S., S.Z. Co-senior authors: M.B., W.K.C., B.D.G., E.G., C.E.S. and R.P.L.

Corresponding authors

Correspondence to Martina Brueckner, Wendy K. Chung, Bruce D. Gelb, Elizabeth Goldmuntz, Christine E. Seidman or Richard P. Lifton.

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The authors declare no competing financial interests.

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Zaidi, S., Choi, M., Wakimoto, H. et al. De novo mutations in histone-modifying genes in congenital heart disease. Nature 498, 220–223 (2013). https://doi.org/10.1038/nature12141

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