Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

Abstract

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent–offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for 5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for 11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including 3% of isolated CHD patients and 28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in 440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

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Figure 1: Q–Q plots comparing observed versus expected P values for recessive genotypes in each gene in cases and controls.
Figure 2: Phenotypes and shared haplotypes among homozygotes for GDF1 c.1091T>C (p.Met364Thr).
Figure 3: FLT4 LoF mutations in TOF.
Figure 4: Chromatin modification genes and genes with multiple damaging DNMs are enriched for high expression in developing heartand intolerance to LoF mutation.

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Acknowledgements

We are grateful to the patients and families who participated in this research. We thank the following people for outstanding contributions to patient recruitment: A. Julian, M. Mac Neal, Y. Mendez, T. Mendiz-Ramdeen and C. Mintz (Icahn School of Medicine at Mount Sinai); N. Cross (Yale School of Medicine); J. Ellashek and N. Tran (Children's Hospital of Los Angeles); B. McDonough, J. Geva and M. Borensztein (Harvard Medical School), K. Flack, L. Panesar and N. Taylor (University College London); E. Taillie (University of Rochester School of Medicine and Dentistry); S. Edman, J. Garbarini, J. Tusi and S. Woyciechowski (Children's Hospital of Philadelphia); D. Awad, C. Breton, K. Celia, C. Duarte, D. Etwaru, N. Fishman, M. Kaspakoval, J. Kline, R. Korsin, A. Lanz, E. Marquez, D. Queen, A. Rodriguez, J. Rose, J.K. Sond, D. Warburton, A. Wilpers and R. Yee (Columbia Medical School). We are grateful to J. Ekstein and D. Yeshorim for provision of anonymized DNA samples. The authors thank S. Wang for critical discussion. This work was supported by U01 HL098153 and grant UL1TR000003 from the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health; grants to the Pediatric Cardiac Genomics Consortium (UM1-HL098147, UM1-HL128761, UM1-HL098123, UM1-HL128711, UM1-HL098162, UO1-HL131003, UO1-HL098188, UO1-HL098153, UO1-HL098163); the NIH Centers for Mendelian Genomics (5U54HG006504); the Howard Hughes Medical Institute (R.P.L. and C.E.S.); and the Simons Foundation (W.K.C.). S.C.J. was supported by the James Hudson Brown-Alexander Brown Coxe Postdoctoral Fellowship at the Yale University School of Medicine. J.H. was supported by the John S. LaDue Fellowship at Harvard Medical School and is a recipient of the Alan Lerner Research Award at the Brigham and Women's Hospital. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute, the National Center for Research Resources or the NIH.

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Contributions

Study design: M.B., W.K.C., M.T.-F., B.D.G., E.G., J.R.K., R.P.L., J.G.S., C.E.S.; cohort ascertainment, phenotypic characterization and recruitment: M.B., W.C., W.K.C., J.D., A.G., B.D.G., E.G., J.W.G., J.H., R.K., S.M., J.W.N., G.A.P., A.E.R., M.W.R., C.E.S.; exome sequencing production and validation: K.B., C.C., R.P.L., S.M.M., I.R.T., J.Z.; exome sequencing analysis: M.B., R.D.B., S.R.D., S.C.J., J.H., W.-C.H., J.K., R.P.L., S.M., S.M.M., H.Q., C.E.S., J.G.S., M.C.S., S.J.S., Y.S., W.S.W., M.Y., S.Z., X.Z.; statistical analysis: J.H., S.C.J., R.P.L., Q.L., S.M., C.E.S., S.W., M.Y., H.Z., S.Z.; biophysical simulation for GDF1: S.H.; writing and review of manuscript: M.B., W.K.C., M.T.-F., B.D.G., E.G., J.H., S.C.J., J.R.K., C.W.L., R.P.L., Q.L., C.E.S., D.S., J.G.S., H.J.Y., S.Z. All authors read and approved the manuscript.

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Correspondence to Richard Kim or Jonathan G Seidman or Bruce D Gelb or Christine E Seidman or Martina Brueckner.

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Jin, S., Homsy, J., Zaidi, S. et al. Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands. Nat Genet 49, 1593–1601 (2017). https://doi.org/10.1038/ng.3970

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