Skip to main content

Thank you for visiting 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.

  • Letter
  • Published:

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


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

Access options

Buy this article

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.

Similar content being viewed by others

Accession codes

Data deposits

Messenger RNA and protein sequences are available in the RefSeq database ( under accession numbers listed in Supplementary Table 4; mutation data are available at dbSNP ( under batch accession 1059065.


  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


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

Authors and Affiliations



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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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.


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