Format

Send to

Choose Destination
Nat Genet. 2016 Sep;48(9):1060-5. doi: 10.1038/ng.3627. Epub 2016 Aug 1.

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

Author information

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.

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.

PMID:
27479907
PMCID:
PMC5988037
DOI:
10.1038/ng.3627
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center