2. Academic Validation
  3. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

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

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.

Figures