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

  • Nat Genet. 2016 Sep;48(9):1060-5. doi: 10.1038/ng.3627.
Alejandro Sifrim  1 ,  Marc-Phillip Hitz  1  2  3 ,  Anna Wilsdon  4 ,  Jeroen Breckpot  5 ,  Saeed H Al Turki  1  6  7 ,  Bernard Thienpont  8  9 ,  Jeremy McRae  1 ,  Tomas W Fitzgerald  1 ,  Tarjinder Singh  1 ,  Ganesh Jawahar Swaminathan  1 ,  Elena Prigmore  1 ,  Diana Rajan  1 ,  Hashim Abdul-Khaliq  10  11 ,  Siddharth Banka  12  13 ,  Ulrike M M Bauer  11 ,  Jamie Bentham  14 ,  Felix Berger  3  11  15 ,  Shoumo Bhattacharya  16 ,  Frances Bu'Lock  17 ,  Natalie Canham  18 ,  Irina-Gabriela Colgiu  1 ,  Catherine Cosgrove  16 ,  Helen Cox  19 ,  Ingo Daehnert  11  20 ,  Allan Daly  1 ,  John Danesh  1  21  22 ,  Alan Fryer  23 ,  Marc Gewillig  24 ,  Emma Hobson  25 ,  Kirstin Hoff  2  3 ,  Tessa Homfray  26 ,  INTERVAL Study ,  Anne-Karin Kahlert  2  3  27 ,  Ami Ketley  4 ,  Hans-Heiner Kramer  2  3  11 ,  Katherine Lachlan  28  29  30 ,  Anne Katrin Lampe  31 ,  Jacoba J Louw  24 ,  Ashok Kumar Manickara  32 ,  Dorin Manase  32 ,  Karen P McCarthy  33 ,  Kay Metcalfe  13 ,  Carmel Moore  22 ,  Ruth Newbury-Ecob  34 ,  Seham Osman Omer  35 ,  Willem H Ouwehand  1  21  36  37 ,  Soo-Mi Park  38 ,  Michael J Parker  39 ,  Thomas Pickardt  11 ,  Martin O Pollard  1 ,  Leema Robert  40 ,  David J Roberts  21  41  42 ,  Jennifer Sambrook  22  36 ,  Kerry Setchfield  4 ,  Brigitte Stiller  11  43 ,  Chris Thornborough  17 ,  Okan Toka  11  44 ,  Hugh Watkins  16 ,  Denise Williams  19 ,  Michael Wright  45 ,  Seema Mital  32 ,  Piers E F Daubeney  46  47 ,  Bernard Keavney  48 ,  Judith Goodship  49 ,  UK10K Consortium ,  Riyadh Mahdi Abu-Sulaiman  35  50  51 ,  Sabine Klaassen  3  11  52  53 ,  Caroline F Wright  1 ,  Helen V Firth  54 ,  Jeffrey C Barrett  1 ,  Koenraad Devriendt  5 ,  David R FitzPatrick  55 ,  J David Brook  4 ,  Deciphering Developmental Disorders Study ,  Matthew E Hurles  1
Affiliations
  • 1. Wellcome Trust Sanger Institute, Cambridge, UK.
  • 2. Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany.
  • 3. German Center for Cardiovascular Research (DZHK), Berlin, Germany.
  • 4. School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
  • 5. Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
  • 6. Department of Pathology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
  • 7. Genetics Training Program, Harvard Medical School, Boston, Massachusetts, USA.
  • 8. Vesalius Research Center, VIB, Leuven, Belgium.
  • 9. Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
  • 10. Department of Pediatric Cardiology, Saarland University, Homburg, Germany.
  • 11. Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.
  • 12. Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
  • 13. Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
  • 14. Department of Paediatric Cardiology, Yorkshire Heart Centre, Leeds, UK.
  • 15. Department of Congenital Heart Disease and Pediatric Cardiology, German Heart Institute Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany.
  • 16. Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.
  • 17. East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK.
  • 18. North West Thames Regional Genetics Centre, London North West Healthcare NHS Trust, Harrow, UK.
  • 19. West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Birmingham, UK.
  • 20. Department of Pediatric Cardiology, Heart Center, University of Leipzig, Leipzig, Germany.
  • 21. NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • 22. INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • 23. Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
  • 24. Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium.
  • 25. Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.
  • 26. South West Thames Regional Genetics Centre, St George's Healthcare NHS Trust, University of London, London, UK.
  • 27. Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, Dresden, Germany.
  • 28. Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK.
  • 29. Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.
  • 30. Faculty of Medicine, University of Southampton, Southampton, UK.
  • 31. South East of Scotland Clinical Genetic Service, IGMM North, Western General Hospital, Edinburgh, UK.
  • 32. Hospital for Sick Children, Toronto, Ontario, Canada.
  • 33. Cardiac Morphology Unit, Royal Brompton Hospital and the National Heart and Lung Institute, Imperial College, UK.
  • 34. Department of Clinical Genetics, St Michael's Hospital, Bristol, UK.
  • 35. Division of Pediatric Cardiology, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.
  • 36. Department of Haematology, University of Cambridge, Cambridge, UK.
  • 37. NHS Blood and Transplant, Cambridge, UK.
  • 38. East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
  • 39. Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield, UK.
  • 40. South East Thames Regional Genetics Centre, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK.
  • 41. NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK.
  • 42. Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
  • 43. Department of Congenital Heart Defects and Pediatric Cardiology, Heart Centre, University of Freiburg, Freiburg, Germany.
  • 44. Friedrich Alexander Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiology, Erlangen, Germany.
  • 45. Northern Genetics Service, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle-upon-Tyne, UK.
  • 46. Division of Paediatric Cardiology, Royal Brompton Hospital, London, UK.
  • 47. Paediatric Cardiology, Imperial College, London, UK.
  • 48. Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.
  • 49. Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
  • 50. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
  • 51. King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.
  • 52. Experimental and Clinical Research Center (ECRC), Charité Medical Faculty and Max Delbruck Center for Molecular Medicine, Berlin, Germany.
  • 53. Department of Pediatric Cardiology, Charité University Medicine, Berlin, Germany.
  • 54. East Anglian Medical Genetics, Cambridge University Hospitals NHS Foundation Trust, Biomedical Campus, Cambridge, UK.
  • 55. Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK.
PMID: 27479907 DOI: 10.1038/ng.3627
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%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. 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 findings. 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.