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.

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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.

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.


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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




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 or Wendy K. Chung or Bruce D. Gelb or Elizabeth Goldmuntz or 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).

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