Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
Nature Genetics
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Sifrim A1, Hitz MP1,2,3, Wilsdon A4, Breckpot J5, Turki SH1,6,7, Thienpont B8,9, McRae J1, Fitzgerald TW1, Singh T1, Swaminathan GJ1, Prigmore E1, Rajan D1, Abdul-Khaliq H10,11, Banka S12,13, Bauer UM11, Bentham J14, Berger F3,11,15, Bhattacharya S16, Bu’Lock F17, Canham N18, Colgiu IG1, Cosgrove C16, Cox H19, Daehnert I11,20, Daly A1, Danesh J1,21,22, Fryer A23, Gewillig M24, Hobson E25, Hoff K2,3, Homfray T26; INTERVAL Study, Kahlert AK2,3,27, Ketley A4, Kramer HH2,3,11, Lachlan K28,29,30, Lampe AK31, Louw JJ24, Manickara AK32, Manase D32, McCarthy KP33, Metcalfe K13, Moore C22, Newbury-Ecob R34, Omer SO35, Ouwehand WH1,21,36,37, Park SM38, Parker MJ39, Pickardt T11, Pollard MO1, Robert L40, Roberts DJ21,41,42, Sambrook J22,36, Setchfield K4, Stiller B11,43, Thornborough C17, Toka O11,44, Watkins H16, Williams D19, Wright M45, Mital S32, Daubeney PE46,47, Keavney B48, Goodship J49; UK10K Consortium, Abu-Sulaiman RM35,50,51, Klaassen S3,11,52,53, Wright CF1, Firth HV54, Barrett JC1, Devriendt K5, FitzPatrick DR55, Brook JD4; Deciphering Developmental Disorders Study, Hurles ME1


1Wellcome Trust Sanger Institute, Cambridge, UK.
2Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany.
3German Center for Cardiovascular Research (DZHK), Berlin, Germany.
4School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, UK.
5Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
6Department of Pathology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
7Genetics Training Program, Harvard Medical School, Boston, Massachusetts, USA.
8Vesalius Research Center, VIB, Leuven, Belgium.
9Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
10Department of Pediatric Cardiology, Saarland University, Homburg, Germany.
11Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.
12Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.
13Manchester Centre for Genomic Medicine, St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
14Department of Paediatric Cardiology, Yorkshire Heart Centre, Leeds, UK.
15Department of Congenital Heart Disease and Pediatric Cardiology, German Heart Institute Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany.
16Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.
17East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK.
18North West Thames Regional Genetics Centre, London North West Healthcare NHS Trust, Harrow, UK.
19West Midlands Regional Genetics Service, Birmingham Women’s NHS Foundation Trust, Birmingham Women’s Hospital, Birmingham, UK.
20Department of Pediatric Cardiology, Heart Center, University of Leipzig, Leipzig, Germany.
21NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
22INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
23Department of Clinical Genetics, Liverpool Women’s NHS Foundation Trust, Liverpool, UK.
24Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium.
25Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.
26South West Thames Regional Genetics Centre, St George’s Healthcare NHS Trust, University of London, London, UK.
27Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, Dresden, Germany.
28Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK.
29Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.
30Faculty of Medicine, University of Southampton, Southampton, UK.
31South East of Scotland Clinical Genetic Service, IGMM North, Western General Hospital, Edinburgh, UK.
32Hospital for Sick Children, Toronto, Ontario, Canada.
33Cardiac Morphology Unit, Royal Brompton Hospital and the National Heart and Lung Institute, Imperial College, UK.
34Department of Clinical Genetics, St Michael’s Hospital, Bristol, UK.
35Division of Pediatric Cardiology, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.
36Department of Haematology, University of Cambridge, Cambridge, UK.
37NHS Blood and Transplant, Cambridge, UK.
38East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
39Sheffield Children’s Hospital NHS Foundation Trust, Western Bank, Sheffield, UK.
40South East Thames Regional Genetics Centre, Guy’s and St Thomas’ NHS Foundation Trust, Guy’s Hospital, London, UK.
41NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK.
42Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
43Department of Congenital Heart Defects and Pediatric Cardiology, Heart Centre, University of Freiburg, Freiburg, Germany.
44Friedrich Alexander Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiology, Erlangen, Germany.
45Northern Genetics Service, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle-upon-Tyne, UK.
46Division of Paediatric Cardiology, Royal Brompton Hospital, London, UK.
47Paediatric Cardiology, Imperial College, London, UK.
48Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.
49Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
50King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
51King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.
52Experimental and Clinical Research Center (ECRC), Charité Medical Faculty and Max Delbruck Center for Molecular Medicine, Berlin, Germany.
53Department of Pediatric Cardiology, Charité University Medicine, Berlin, Germany.
54East Anglian Medical Genetics, Cambridge University Hospitals NHS Foundation Trust, Biomedical Campus, Cambridge, UK.
55Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK.

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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 ( approximately 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.