Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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

Subjects

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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

Accession codes

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.

References

  1. Reller, M. D., Strickland, M. J., Riehle-Colarusso, T., Mahle, W. T. & Correa, A. Prevalence of congenital heart defects in metropolitan Atlanta, 1998–2005. J. Pediatr. 153, 807–813 (2008)

    Article  Google Scholar 

  2. Shilatifard, A. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu. Rev. Biochem. 81, 65–95 (2012)

    Article  CAS  Google Scholar 

  3. Pedersen, M. T. & Helin, K. Histone demethylases in development and disease. Trends Cell Biol. 20, 662–671 (2010)

    Article  CAS  Google Scholar 

  4. Fuchs, G. et al. RNF20 and USP44 regulate stem cell differentiation by modulating H2B monoubiquitylation. Mol. Cell 46, 662–673 (2012)

    Article  CAS  Google Scholar 

  5. Dahle, Ø., Kumar, A. & Kuehn, M. R. Nodal signaling recruits the histone demethylase Jmjd3 to counteract polycomb-mediated repression at target genes. Sci. Signal. 3, ra48 (2010)

    Article  Google Scholar 

  6. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006)

    Article  CAS  Google Scholar 

  7. Pediatric Cardiac Genomics Consortium. The Congenital Heart Disease Network Study (CHD GENES): rationale, design and early results. Circ. Res. 112, 698–706 (2013)

  8. Boyden, L. M. et al. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482, 98–102 (2012)

    Article  ADS  CAS  Google Scholar 

  9. Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012)

    Article  ADS  CAS  Google Scholar 

  10. Scally, A. & Durbin, R. Revising the human mutation rate: implications for understanding human evolution. Nature Rev. Genet. 13, 745–753 (2012)

    Article  CAS  Google Scholar 

  11. Lederer, D. et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am. J. Hum. Genet. 90, 119–124 (2012)

    Article  CAS  Google Scholar 

  12. Vissers, L. E. et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nature Genet. 36, 955–957 (2004)

    Article  CAS  Google Scholar 

  13. Gendron, R. L., Adams, L. C. & Paradis, H. Tubedown-1, a novel acetyltransferase associated with blood vessel development. Dev. Dyn. 218, 300–315 (2000)

    Article  CAS  Google Scholar 

  14. Greenway, S. C. et al. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nature Genet. 41, 931–935 (2009)

    Article  CAS  Google Scholar 

  15. Wamstad, J. A. et al. Dynamic and coordinated epigenetic regulation of developmental transitions in the cardiac lineage. Cell 151, 206–220 (2012)

    Article  CAS  Google Scholar 

  16. Paige, S. L. et al. A temporal chromatin signature in human embryonic stem cells identifies regulators of cardiac development. Cell 151, 221–232 (2012)

    Article  CAS  Google Scholar 

  17. Ceol, C. J. et al. The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset. Nature 471, 513–517 (2011)

    Article  ADS  CAS  Google Scholar 

  18. Sausen, M. et al. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nature Genet. 45, 12–17 (2013)

    Article  CAS  Google Scholar 

  19. O'Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485, 246–250 (2012)

    Article  ADS  CAS  Google Scholar 

  20. Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012)

    Article  CAS  Google Scholar 

  21. Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012)

    Article  ADS  CAS  Google Scholar 

  22. O’Roak, B. J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338, 1619–1622 (2012)

    Article  ADS  Google Scholar 

  23. Kong, A. et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488, 471–475 (2012)

    Article  ADS  CAS  Google Scholar 

  24. Vorstman, J. A., Breetvelt, E. J., Thode, K. I., Chow, E. W. & Bassett, A. S. Expression of autism spectrum and schizophrenia in patients with a 22q11.2 deletion. Schizophr. Res. 143, 55–59 (2013)

    Article  Google Scholar 

  25. Mefford, H. C. et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N. Engl. J. Med. 359, 1685–1699 (2008)

    Article  CAS  Google Scholar 

  26. Ghebranious, N., Giampietro, P. F., Wesbrook, F. P. & Rezkalla, S. H. A novel microdeletion at 16p11.2 harbors candidate genes for aortic valve development, seizure disorder, and mild mental retardation. Am. J. Med. Genet. 143A, 1462–1471 (2007)

    Article  CAS  Google Scholar 

  27. Soemedi, R. et al. Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease. Am. J. Hum. Genet. 91, 489–501 (2012)

    Article  CAS  Google Scholar 

  28. Fischbach, G. D. & Lord, C. The Simons Simplex Collection: a resource for identification of autism genetic risk factors. Neuron 68, 192–195 (2010)

    Article  CAS  Google Scholar 

  29. Christodoulou, D. C., Gorham, J. M., Herman, D. S. & Seidman, J. G. Construction of normalized RNA-seq libraries for next-generation sequencing using the crab duplex-specific nuclease. Curr. Protoc. Mol. Biol. 94:4.12.1–4.12.11. (2011)

  30. Herman, D. S. et al. Truncations of titin causing dilated cardiomyopathy. N. Engl. J. Med. 366, 619–628 (2012)

    Article  CAS  Google Scholar 

Download references

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
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Murim Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroko Wakimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lijiang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jianming Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John D. Overton
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Angela Romano-Adesman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Robert D. Bjornson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roger E. Breitbart
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kerry K. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nicholas J. Carriero
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yee Him Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. John Deanfield
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Steve DePalma
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Khalid A. Fakhro
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Joseph Glessner
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Hakon Hakonarson
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Michael J. Italia
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Jonathan R. Kaltman
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Juan Kaski
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Richard Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Jennie K. Kline
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Teresa Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Jeremy Leipzig
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Alexander Lopez
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Shrikant M. Mane
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Laura E. Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Jane W. Newburger
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Michael Parfenov
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Itsik Pe’er
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. George Porter
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Amy E. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Ravi Sachidanandam
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Stephan J. Sanders
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Howard S. Seiden
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Mathew W. State
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Sailakshmi Subramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  38. Irina R. Tikhonova
    View author publications

    You can also search for this author in PubMed Google Scholar

  39. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  40. Dorothy Warburton
    View author publications

    You can also search for this author in PubMed Google Scholar

  41. Peter S. White
    View author publications

    You can also search for this author in PubMed Google Scholar

  42. Ismee A. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  43. Hongyu Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  44. Jonathan G. Seidman
    View author publications

    You can also search for this author in PubMed Google Scholar

  45. Martina Brueckner
    View author publications

    You can also search for this author in PubMed Google Scholar

  46. Wendy K. Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  47. Bruce D. Gelb
    View author publications

    You can also search for this author in PubMed Google Scholar

  48. Elizabeth Goldmuntz
    View author publications

    You can also search for this author in PubMed Google Scholar

  49. Christine E. Seidman
    View author publications

    You can also search for this author in PubMed Google Scholar

  50. Richard P. Lifton
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data, Supplementary Tables 1-13 and Supplementary Figures 1-9. (PDF 2282 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature12141

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing