Letter | Published:

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Nature Genetics volume 48, pages 10601065 (2016) | Download Citation

Abstract

Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (2.7%)3, suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance4,5. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations6,7. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings8. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

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Acknowledgements

We thank the patients and their families for their participation and patience. The authors thank J. Lord for proofreading this manuscript and the Exome Aggregation Consortium for making their data available. The Deciphering Developmental Disorders study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the UK Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the UK Department of Health. The research team acknowledges the support of the National Institutes for Health Research through the Comprehensive Clinical Research Network. The authors wish to thank the Sanger Human Genome Informatics team, the DNA pipelines team and the Core Sequencing team for their support in generating and processing the data. We would like to thank the Pediatric Cardiac Genomics Consortium (PCGC) and dbGAP for making the data publicly available. This study was supported by the German Center for Cardiovascular Research (DZHK) partner sites Berlin, Kiel and Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects. Participants in the INTERVAL randomized controlled trial were recruited with the active collaboration of NHS Blood and Transplant England, which has supported field work and other elements of the trial. DNA extraction and genotyping was funded by the National Institute of Health Research (NIHR), the NIHR BioResource and the NIHR Cambridge Biomedical Research Centre. The academic coordinating center for INTERVAL was supported by core funding from the NIHR Blood and Transplant Research Unit in Donor Health and Genomics, UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), and NIHR Research Cambridge Biomedical Research Centre. J.D.B., K.S. and A.K. are funded by British Heart Foundation Programme Grant RG/13/10/30376. A.W. is funded by a British Heart Foundation Clinical Fellowship FS/14/51/30879. D.R.F. is funded through an MRC Human Genetics Unit program grant to the University of Edinburgh. S.H.A.T., S.O.O. and R.M.A.-S. were supported by funding from King Abdullah International Medical Research Center (grant number RC12/037). J.B. was supported by the Klinisch Onderzoeksfonds UZ; B.T. was supported by the CHAMELEO Marie Curie Career Integration Grant; J.J.L. and M.G. Eddy Merckx Research grant. K.D. was funded by the GOA/2012/015 grant. A.K.M., D.M. and S.M. were supported by the Heart and Stroke Foundation of Ontario, Canadian Institutes of Health Research.

Author information

Author notes

    • Alejandro Sifrim
    •  & Marc-Phillip Hitz

    These authors contributed equally to this work.

Affiliations

  1. Wellcome Trust Sanger Institute, Cambridge, UK.

    • Alejandro Sifrim
    • , Marc-Phillip Hitz
    • , Saeed H Al Turki
    • , Jeremy McRae
    • , Tomas W Fitzgerald
    • , Tarjinder Singh
    • , Ganesh Jawahar Swaminathan
    • , Elena Prigmore
    • , Diana Rajan
    • , Irina-Gabriela Colgiu
    • , Allan Daly
    • , John Danesh
    • , Willem H Ouwehand
    • , Martin O Pollard
    • , Caroline F Wright
    • , Jeffrey C Barrett
    •  & Matthew E Hurles
  2. Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig–Holstein Kiel, Kiel, Germany.

    • Marc-Phillip Hitz
    • , Kirstin Hoff
    • , Anne-Karin Kahlert
    •  & Hans-Heiner Kramer
  3. German Center for Cardiovascular Research (DZHK), Berlin, Germany.

    • Marc-Phillip Hitz
    • , Felix Berger
    • , Kirstin Hoff
    • , Anne-Karin Kahlert
    • , Hans-Heiner Kramer
    •  & Sabine Klaassen
  4. School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK.

    • Anna Wilsdon
    • , Ami Ketley
    • , Kerry Setchfield
    •  & J David Brook
  5. Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.

    • Jeroen Breckpot
    •  & Koenraad Devriendt
  6. Department of Pathology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.

    • Saeed H Al Turki
  7. Genetics Training Program, Harvard Medical School, Boston, Massachusetts, USA.

    • Saeed H Al Turki
  8. Vesalius Research Center, VIB, Leuven, Belgium.

    • Bernard Thienpont
  9. Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.

    • Bernard Thienpont
  10. Department of Pediatric Cardiology, Saarland University, Homburg, Germany.

    • Hashim Abdul-Khaliq
  11. Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.

    • Hashim Abdul-Khaliq
    • , Ulrike M M Bauer
    • , Felix Berger
    • , Ingo Daehnert
    • , Hans-Heiner Kramer
    • , Thomas Pickardt
    • , Brigitte Stiller
    • , Okan Toka
    •  & Sabine Klaassen
  12. Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.

    • Siddharth Banka
  13. Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

    • Siddharth Banka
    •  & Kay Metcalfe
  14. Department of Paediatric Cardiology, Yorkshire Heart Centre, Leeds, UK.

    • Jamie Bentham
  15. Department of Congenital Heart Disease and Pediatric Cardiology, German Heart Institute Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany.

    • Felix Berger
  16. Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.

    • Shoumo Bhattacharya
    • , Catherine Cosgrove
    •  & Hugh Watkins
  17. East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK.

    • Frances Bu'Lock
    •  & Chris Thornborough
  18. North West Thames Regional Genetics Centre, London North West Healthcare NHS Trust, Harrow, UK.

    • Natalie Canham
  19. West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Birmingham, UK.

    • Helen Cox
    •  & Denise Williams
  20. Department of Pediatric Cardiology, Heart Center, University of Leipzig, Leipzig, Germany.

    • Ingo Daehnert
  21. NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • John Danesh
    • , Willem H Ouwehand
    •  & David J Roberts
  22. INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • John Danesh
    • , Carmel Moore
    •  & Jennifer Sambrook
  23. Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.

    • Alan Fryer
  24. Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium.

    • Marc Gewillig
    •  & Jacoba J Louw
  25. Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.

    • Emma Hobson
  26. South West Thames Regional Genetics Centre, St George's Healthcare NHS Trust, University of London, London, UK.

    • Tessa Homfray
  27. Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, Dresden, Germany.

    • Anne-Karin Kahlert
  28. Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK.

    • Katherine Lachlan
  29. Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.

    • Katherine Lachlan
  30. Faculty of Medicine, University of Southampton, Southampton, UK.

    • Katherine Lachlan
  31. South East of Scotland Clinical Genetic Service, IGMM North, Western General Hospital, Edinburgh, UK.

    • Anne Katrin Lampe
  32. Hospital for Sick Children, Toronto, Ontario, Canada.

    • Ashok Kumar Manickara
    • , Dorin Manase
    •  & Seema Mital
  33. Cardiac Morphology Unit, Royal Brompton Hospital and the National Heart and Lung Institute, Imperial College, UK.

    • Karen P McCarthy
  34. Department of Clinical Genetics, St Michael's Hospital, Bristol, UK.

    • Ruth Newbury-Ecob
  35. Division of Pediatric Cardiology, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, Ministry of National Guard–Health Affairs, Riyadh, Saudi Arabia.

    • Seham Osman Omer
  36. Department of Haematology, University of Cambridge, Cambridge, UK.

    • Willem H Ouwehand
    •  & Jennifer Sambrook
  37. NHS Blood and Transplant, Cambridge, UK.

    • Willem H Ouwehand
  38. East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.

    • Soo-Mi Park
  39. Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield, UK.

    • Michael J Parker
  40. South East Thames Regional Genetics Centre, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK.

    • Leema Robert
  41. NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK.

    • David J Roberts
  42. Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.

    • David J Roberts
  43. Department of Congenital Heart Defects and Pediatric Cardiology, Heart Centre, University of Freiburg, Freiburg, Germany.

    • Brigitte Stiller
  44. Friedrich Alexander Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiology, Erlangen, Germany.

    • Okan Toka
  45. Northern Genetics Service, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle-upon-Tyne, UK.

    • Michael Wright
  46. Division of Paediatric Cardiology, Royal Brompton Hospital, London, UK.

    • Piers E F Daubeney
  47. Paediatric Cardiology, Imperial College, London, UK.

    • Piers E F Daubeney
  48. Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.

    • Bernard Keavney
  49. Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.

    • Judith Goodship
  50. Division of Pediatric Cardiology, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, Ministry of National Guard–Health Affairs, Riyadh, Saudi Arabia.

    • Riyadh Mahdi Abu-Sulaiman
  51. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.

    • Riyadh Mahdi Abu-Sulaiman
  52. King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.

    • Riyadh Mahdi Abu-Sulaiman
  53. Experimental and Clinical Research Center (ECRC), Charité Medical Faculty and Max Delbruck Center for Molecular Medicine, Berlin, Germany.

    • Sabine Klaassen
  54. Department of Pediatric Cardiology, Charité University Medicine, Berlin, Germany.

    • Sabine Klaassen
  55. East Anglian Medical Genetics, Cambridge University Hospitals NHS Foundation Trust, Biomedical Campus, Cambridge, UK.

    • Helen V Firth
  56. Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • David R FitzPatrick

Consortia

  1. the INTERVAL Study

    A list of members and affiliations appears in the Supplementary Note.

  2. the UK10K Consortium

    A list of members and affiliations appears in the Supplementary Note.

  3. the Deciphering Developmental Disorders Study

    A list of members and affiliations appears in the Supplementary Note.

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Contributions

A.W., J.B., S.H.A.T., B.T., H.A.-K., S. Banka, U.M.M.B., J.B., F. Berger, S. Bhattacharya., F. Bu'Lock, N.C., C.C., H.C., I.D., J.D., A.F., M.G., E.H., K.H., T.H., A.-K.K., H.-H.K., K.L., A.K.L., J.J.L., A.K.M., K.M., C.M., R.N.-E., S.O.O., W.H.O., S.-M.P., M.J.P., T.P., L.R., D.J.R., J.S., K.S., B.S., C.T., O.T., H.W., D.W., M.W., S.M., P.E.F.D., B.K., J.G., R.M.A.-S., S.K., C.F.W., H.V.F., K.D., D.R.F. and J.D.B. recruited the patients. M-P.H., A.W., J.B., H.A.-K., S. Banka, U.M.M.B., J.B., F. Berger, S. Bhattacharya, F. Bu'Lock, N.C., C.C., H.C., I.D., A.F., M.G., E.H., T.H., A.-K.K., H.-H.K., K.L., A.K.L., J.J.L., A.K.M., K.P.M., K.M., R.N.-E., S.O.O., S.-M.P., M.J.P., L.R., K.S., B.S., C.T., O.T., H.W., D.W., M.W., S.M., P.E.F.D., B.K., J.G., R.M.A.-S., S.K., C.F.W., H.V.F., K.D., D.R.F. and J.D.B. participated in initial phenotyping or classification of patients. A.W., J.B., S.H.A.T., B.T., K.H., A.K., D.M., K.P.M., T.P. and K.S. performed sample preparation. M.-P.H., S.H.A.T., E.P., D.R. and K.H. performed validation experiments. A.S., M.-P.H., S.H.A.T., S.M., P.E.F.D., B.K., J.G., R.M.A.-S., S.K., C.F.W., H.V.F., J.C.B., K.D., D.R.F., J.D.B. and M.E.H. designed the study. A.S., M.-P.H., A.W., J.B., S.H.A.T., J.M., T.W.F., T.S., G.J.S., I.-G.C., A.D., M.O.P., J.C.B. and M.E.H. designed and developed the analysis strategy. A.S., M.-P.H., A.W., J.B., S.H.A.T., B.T., J.M., T.W.F., T.S., G.J.S., C.F.W., H.V.F., J.C.B., K.D., D.R.F., J.D.B. and M.E.H. interpreted the results. A.S., M.-P.H., A.W., J.D.B. and M.E.H. wrote the manuscript. M.E.H. supervised the project.

Competing interests

M.E.H. is a cofounder of and holds shares in Congenica Ltd., a genetics diagnostic company.

Corresponding author

Correspondence to Matthew E Hurles.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–14

  2. 2.

    Supplementary Note

    Supplementary Note and Supplementary Tables 1–6, 13, 14, 19, 24 and 27

Excel files

  1. 1.

    Supplementary Table 7

    Inherited rare PTVs in Tier 1 monoallelic CHD genes

  2. 2.

    Supplementary Table 8

    Results of de novo enrichment analysis in the S-CHD cohort

  3. 3.

    Supplementary Table 9

    Results of de novo enrichment analysis in the "unresolved" S-CHD cohort

  4. 4.

    Supplementary Table 10

    Clinical description of probands carrying de novo mutations in CDK13

  5. 5.

    Supplementary Table 11

    Clinical description of probands carrying de novo mutations in CHD4

  6. 6.

    Supplementary Table 12

    Clinical description of probands carrying de novo mutations in PRKD1

  7. 7.

    Supplementary Table 15

    Manual review of top-ranking genes from the (TADA) integrated de novo and inherited variant analysis

  8. 8.

    Supplementary Table 16

    Results of InnateDB Gene Ontology overrepresentation analysis

  9. 9.

    Supplementary Table 17

    Results of InnateDB Pathway overrepresentation analysis

  10. 10.

    Supplementary Table 18

    Overview of main analyses and their primary conclusions

  11. 11.

    Supplementary Table 20

    Manually curated set of known CHD-genes by tier and inheritance mode

  12. 12.

    Supplementary Table 21

    List of de novo variants in S-CHD cases called by DeNovoGear after filtering criteria were applied

  13. 13.

    Supplementary Table 22

    List of de novo variants in NS-CHD cases called by DeNovoGear after filtering criteria were applied

  14. 14.

    Supplementary Table 23

    List of de novo variants in S-CHD-DX cases (syndromic cases with no de novo variants in known developmental disorder genes) called by DeNovoGear after filtering criteria were applied

  15. 15.

    Supplementary Table 25

    1241 rare CNV calls made by CoNVex and passing automatic and manual quality control

  16. 16.

    Supplementary Table 26

    31 CNV calls overlapping known CHD-associated genes or top-ranking genes (FDR<10%) from the integrated de novo and inherited variant analysis

  17. 17.

    Supplementary Table 28

    Results of the integrated (TADA) de novo and inherited rare variant analysis

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DOI

https://doi.org/10.1038/ng.3627

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