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

Autor: Sifrim A; Wellcome Trust Sanger Institute, Cambridge, UK., Hitz MP; 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., Wilsdon A; School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK., Breckpot J; Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium., Turki SH; 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., Thienpont B; Vesalius Research Center, VIB, Leuven, Belgium.; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium., McRae J; Wellcome Trust Sanger Institute, Cambridge, UK., Fitzgerald TW; Wellcome Trust Sanger Institute, Cambridge, UK., Singh T; Wellcome Trust Sanger Institute, Cambridge, UK., Swaminathan GJ; Wellcome Trust Sanger Institute, Cambridge, UK., Prigmore E; Wellcome Trust Sanger Institute, Cambridge, UK., Rajan D; Wellcome Trust Sanger Institute, Cambridge, UK., Abdul-Khaliq H; Department of Pediatric Cardiology, Saarland University, Homburg, Germany.; Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany., Banka S; 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., Bauer UM; Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany., Bentham J; Department of Paediatric Cardiology, Yorkshire Heart Centre, Leeds, UK., Berger F; 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., Bhattacharya S; Department of Cardiovascular Medicine, University of Oxford, Oxford, UK., Bu'Lock F; East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK., Canham N; North West Thames Regional Genetics Centre, London North West Healthcare NHS Trust, Harrow, UK., Colgiu IG; Wellcome Trust Sanger Institute, Cambridge, UK., Cosgrove C; Department of Cardiovascular Medicine, University of Oxford, Oxford, UK., Cox H; West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Birmingham, UK., Daehnert I; 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., Daly A; Wellcome Trust Sanger Institute, Cambridge, UK., Danesh J; 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., Fryer A; Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK., Gewillig M; Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium., Hobson E; Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK., Hoff K; Department of Congenital Heart Disease and Pediatric Cardiology, Universitätsklinikum Schleswig-Holstein Kiel, Kiel, Germany.; German Center for Cardiovascular Research (DZHK), Berlin, Germany., Homfray T; South West Thames Regional Genetics Centre, St George's Healthcare NHS Trust, University of London, London, UK., Kahlert AK; 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., Ketley A; School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK., Kramer HH; 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., Lachlan K; 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., Lampe AK; South East of Scotland Clinical Genetic Service, IGMM North, Western General Hospital, Edinburgh, UK., Louw JJ; Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium., Manickara AK; Hospital for Sick Children, Toronto, Ontario, Canada., Manase D; Hospital for Sick Children, Toronto, Ontario, Canada., McCarthy KP; Cardiac Morphology Unit, Royal Brompton Hospital and the National Heart and Lung Institute, Imperial College, UK., Metcalfe K; Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK., Moore C; INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Newbury-Ecob R; Department of Clinical Genetics, St Michael's Hospital, Bristol, UK., Omer SO; Division of Pediatric Cardiology, King Abdulaziz Cardiac Center, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia., Ouwehand WH; 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., Park SM; East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK., Parker MJ; Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield, UK., Pickardt T; Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany., Pollard MO; Wellcome Trust Sanger Institute, Cambridge, UK., Robert L; South East Thames Regional Genetics Centre, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK., Roberts DJ; 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., Sambrook J; INTERVAL Coordinating Centre, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Department of Haematology, University of Cambridge, Cambridge, UK., Setchfield K; School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK., Stiller B; 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., Thornborough C; East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester, UK., Toka O; 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., Watkins H; Department of Cardiovascular Medicine, University of Oxford, Oxford, UK., Williams D; West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Birmingham, UK., Wright M; Northern Genetics Service, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle-upon-Tyne, UK., Mital S; Hospital for Sick Children, Toronto, Ontario, Canada., Daubeney PE; Division of Paediatric Cardiology, Royal Brompton Hospital, London, UK.; Paediatric Cardiology, Imperial College, London, UK., Keavney B; Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK., Goodship J; Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK., Abu-Sulaiman RM; 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., Klaassen S; 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., Wright CF; Wellcome Trust Sanger Institute, Cambridge, UK., Firth HV; East Anglian Medical Genetics, Cambridge University Hospitals NHS Foundation Trust, Biomedical Campus, Cambridge, UK., Barrett JC; Wellcome Trust Sanger Institute, Cambridge, UK., Devriendt K; Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium., FitzPatrick DR; Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK., Brook JD; School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, UK., Hurles ME; Wellcome Trust Sanger Institute, Cambridge, UK.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2016 Sep; Vol. 48 (9), pp. 1060-5. Date of Electronic Publication: 2016 Aug 01.
DOI: 10.1038/ng.3627
Abstrakt: 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.
Databáze: MEDLINE