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

  • Nature Genetics volume 49, pages 15931601 (2017)
  • doi:10.1038/ng.3970
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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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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.

Author information

Author notes

    • Sheng Chih Jin
    • , Jason Homsy
    •  & Samir Zaidi

    These authors contributed equally to this work.

    • Christine E Seidman
    • , Richard P Lifton
    •  & Martina Brueckner

    These authors jointly directed this project.


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

    • Sheng Chih Jin
    • , Samir Zaidi
    • , Xue Zeng
    • , Michael C Sierant
    • , Wei-Chien Hung
    • , Junhui Zhang
    • , Richard P Lifton
    •  & Martina Brueckner
  2. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Jason Homsy
    • , Steven R DePalma
    • , Jonathan G Seidman
    •  & Christine E Seidman
  3. Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Jason Homsy
    •  & Christine E Seidman
  4. Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA.

    • Qiongshi Lu
    •  & Hongyu Zhao
  5. Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Sarah Morton
  6. Department of Applied Physics and Applied Mathematics, Columbia University, New York, New York, USA.

    • Hongjian Qi
  7. Department of Pediatrics, Columbia University Medical Center, New York, New York, USA.

    • Weni Chang
  8. Department of Computational Chemistry, University College London School of Pharmacy, London, UK.

    • Shozeb Haider
  9. Yale Center for Genome Analysis, Yale University, New Haven, Connecticut, USA.

    • James Knight
    • , Robert D Bjornson
    • , Christopher Castaldi
    • , Irina R Tikhonoa
    • , Kaya Bilguvar
    •  & Shrikant M Mane
  10. Department of Psychiatry, University of California San Francisco, San Francisco, California, USA.

    • Stephan J Sanders
  11. Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

    • Seema Mital
  12. Division of Pediatric Cardiology, University of Michigan, Ann Arbor, Michigan, USA.

    • Mark W Russell
  13. Department of Pediatric Cardiac Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • J William Gaynor
  14. Department of Cardiology, University College London and Great Ormond Street Hospital, London, UK.

    • John Deanfield
    •  & Alessandro Giardini
  15. Department of Pediatrics, University of Rochester Medical Center, The School of Medicine and Dentistry, Rochester, New York, USA.

    • George A Porter Jr
  16. Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.

    • Deepak Srivastava
  17. Roddenberry Stem Cell Center at Gladstone, San Francisco, California, USA.

    • Deepak Srivastava
  18. Departments of Pediatrics and Biochemistry & Biophysics, University of California, San Francisco, San Francisco, California, USA.

    • Deepak Srivastava
  19. Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.

    • Cecelia W Lo
  20. Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, New York, USA.

    • Yufeng Shen
  21. Department of Human Genetics, Eccles Institute of Human Genetics, University of Utah and School of Medicine, Salt Lake City, Utah, USA.

    • W Scott Watkins
    • , Mark Yandell
    •  & H Joseph Yost
  22. USTAR Center for Genetic Discovery, University of Utah, Salt Lake City, Utah, USA.

    • Mark Yandell
  23. Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah, USA.

    • Martin Tristani-Firouzi
  24. Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA.

    • Jane W Newburger
    •  & Amy E Roberts
  25. Pediatric Cardiac Surgery, Children's Hospital of Los Angeles, Los Angeles, California, USA.

    • Richard Kim
  26. Heart Development and Structural Diseases Branch, Division of Cardiovascular Sciences, NHLBI/NIH, Bethesda, Maryland, USA.

    • Jonathan R Kaltman
  27. Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Elizabeth Goldmuntz
  28. Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York, USA.

    • Wendy K Chung
  29. Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

    • Bruce D Gelb
  30. Howard Hughes Medical Institute, Harvard University, Boston, Massachusetts, USA.

    • Christine E Seidman
  31. Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York, USA.

    • Richard P Lifton
  32. Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Martina Brueckner


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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

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