title: Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.
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.
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Alejandro
authors.identifier: 0000-0001-8247-4020
authors.initials: A
authors.lastname: Sifrim
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.|Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany.|German Center for Cardiovascular Research (DZHK), Berlin, Germany.
authors.forename: Marc-Phillip
authors.initials: MP
authors.lastname: Hitz
authors.affiliation: School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Wilsdon
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Breckpot
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.|Department of Pathology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.|Genetics Training Program, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Saeed H Al
authors.initials: SH
authors.lastname: Turki
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Bernard
authors.identifier: 0000-0002-8772-6845
authors.initials: B
authors.lastname: Thienpont
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: McRae
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Tomas W
authors.initials: TW
authors.lastname: Fitzgerald
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Tarjinder
authors.initials: T
authors.lastname: Singh
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Ganesh Jawahar
authors.initials: GJ
authors.lastname: Swaminathan
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Prigmore
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Rajan
authors.affiliation: Department of Pediatric Cardiology, Saarland University, Homburg, Germany.|Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.
authors.forename: Hashim
authors.initials: H
authors.lastname: Abdul-Khaliq
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.|Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
authors.forename: Siddharth
authors.identifier: 0000-0002-8527-2210
authors.initials: S
authors.lastname: Banka
authors.affiliation: Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.
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authors.initials: UM
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authors.affiliation: Department of Paediatric Cardiology, Yorkshire Heart Centre, Leeds, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Bentham
authors.affiliation: German Center for Cardiovascular Research (DZHK), Berlin, Germany.|Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.|Department of Congenital Heart Disease and Pediatric Cardiology, German Heart Institute Berlin, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Berger
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.
authors.forename: Shoumo
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authors.affiliation: East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK.
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authors.initials: F
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authors.affiliation: North West Thames Regional Genetics Centre, London North West Healthcare NHS Trust, Harrow, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Canham
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Irina-Gabriela
authors.initials: IG
authors.lastname: Colgiu
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, Oxford, UK.
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authors.initials: C
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authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Birmingham, UK.
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authors.initials: H
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authors.affiliation: Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.|Department of Pediatric Cardiology, Heart Center, University of Leipzig, Leipzig, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Daehnert
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
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authors.initials: A
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authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.|NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
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authors.initials: J
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authors.affiliation: Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
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authors.affiliation: Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium.
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authors.initials: E
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authors.affiliation: Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany.|German Center for Cardiovascular Research (DZHK), Berlin, Germany.
authors.forename: Kirstin
authors.initials: K
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authors.affiliation: South West Thames Regional Genetics Centre, St George's Healthcare NHS Trust, University of London, London, UK.
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authors.lastname: Homfray
authors.affiliation: Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany.|German Center for Cardiovascular Research (DZHK), Berlin, Germany.|Institute for Clinical Genetics, Carl Gustav Carus Faculty of Medicine, Dresden, Germany.
authors.forename: Anne-Karin
authors.initials: AK
authors.lastname: Kahlert
authors.affiliation: School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
authors.forename: Ami
authors.initials: A
authors.lastname: Ketley
authors.affiliation: Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany.|German Center for Cardiovascular Research (DZHK), Berlin, Germany.|Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.
authors.forename: Hans-Heiner
authors.initials: HH
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authors.affiliation: Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK.|Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.|Faculty of Medicine, University of Southampton, Southampton, UK.
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authors.affiliation: South East of Scotland Clinical Genetic Service, IGMM North, Western General Hospital, Edinburgh, UK.
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authors.affiliation: Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Jacoba J
authors.initials: JJ
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authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Hospital for Sick Children, Toronto, Ontario, Canada.
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authors.affiliation: Cardiac Morphology Unit, Royal Brompton Hospital and the National Heart and Lung Institute, Imperial College, UK.
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authors.affiliation: Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
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authors.affiliation: INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
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authors.affiliation: Department of Clinical Genetics, St Michael's Hospital, Bristol, UK.
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authors.initials: R
authors.lastname: Newbury-Ecob
authors.affiliation: Division of Pediatric Cardiology, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.
authors.forename: Seham Osman
authors.initials: SO
authors.lastname: Omer
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.|NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|Department of Haematology, University of Cambridge, Cambridge, UK.|NHS Blood and Transplant, Cambridge, UK.
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authors.initials: WH
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authors.affiliation: East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
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authors.affiliation: Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield, UK.
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authors.affiliation: Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.
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authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
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authors.identifier: 0000-0001-8738-0920
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authors.affiliation: NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.|NHS Blood and Transplant, John Radcliffe Hospital, Oxford, UK.|Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
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authors.affiliation: Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.|Department of Congenital Heart Defects and Pediatric Cardiology, Heart Centre, University of Freiburg, Freiburg, Germany.
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authors.affiliation: Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.|Friedrich Alexander Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiology, Erlangen, Germany.
authors.forename: Okan
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authors.identifier: 0000-0002-7643-4484
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authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.
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authors.identifier: 0000-0001-9573-0812
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authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Judith
authors.initials: J
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authors.affiliation: Division of Pediatric Cardiology, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.|King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.|King Abdullah International Medical Research Center (KAIMRC), Riyadh, Saudi Arabia.
authors.forename: Riyadh Mahdi
authors.initials: RM
authors.lastname: Abu-Sulaiman
authors.affiliation: German Center for Cardiovascular Research (DZHK), Berlin, Germany.|Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany.|Experimental and Clinical Research Center (ECRC), Charité Medical Faculty and Max Delbruck Center for Molecular Medicine, Berlin, Germany.|Department of Pediatric Cardiology, Charité University Medicine, Berlin, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klaassen
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
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authors.initials: CF
authors.lastname: Wright
authors.affiliation: East Anglian Medical Genetics, Cambridge University Hospitals NHS Foundation Trust, Biomedical Campus, Cambridge, UK.
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authors.initials: HV
authors.lastname: Firth
authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Jeffrey C
authors.identifier: 0000-0002-1152-370X
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Koenraad
authors.initials: K
authors.lastname: Devriendt
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: FitzPatrick
authors.affiliation: School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
authors.forename: J David
authors.initials: JD
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authors.affiliation: Wellcome Trust Sanger Institute, Cambridge, UK.
authors.forename: Matthew E
authors.initials: ME
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mesh_terms: D001324:Autoantigens / Q000235:genetics*; D016203:CDC2 Protein Kinase / Q000737:chemistry / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D008297:Male; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D011493:Protein Kinase C / Q000235:genetics*; D017384:Sequence Deletion; D013577:Syndrome
chemical_list: D001324:Autoantigens; C115323:CHD4 protein, human; C089212:protein kinase D; D011493:Protein Kinase C; D016203:CDC2 Protein Kinase; C072262:CDK13 protein, human; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex