期刊
NATURE GENETICS
卷 48, 期 9, 页码 1060-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3627
关键词
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资金
- Health Innovation Challenge Fund [HICF-1009-003]
- Wellcome Trust
- UK Department of Health
- Wellcome Trust Sanger Institute [WT098051]
- National Institutes for Health Research through the Comprehensive Clinical Research Network
- German Center for Cardiovascular Research (DZHK) partner sites Berlin, Kiel
- National Institute of Health Research (NIHR)
- NIHR BioResource
- NIHR Cambridge Biomedical Research Centre
- NIHR Blood and Transplant Research Unit in Donor Health and Genomics
- UK Medical Research Council [G0800270]
- British Heart Foundation [SP/09/002]
- NIHR Research Cambridge Biomedical Research Centre
- British Heart Foundation Programme Grant [RG/13/10/30376]
- British Heart Foundation Clinical Fellowship [FS/14/51/30879]
- MRC Human Genetics Unit program grant
- King Abdullah International Medical Research Center [RC12/037]
- Klinisch Onderzoeksfonds
- CHAMELEO Marie Curie Career Integration Grant
- Eddy Merckx Research grant
- Heart and Stroke Foundation of Ontario, Canadian Institutes of Health Research
- Competence Network for Congenital Heart Defects
- National Register for Congenital Heart Defects
- [GOA/2012/015]
- MRC [G0800270, MC_PC_U127561093, MR/L003120/1] Funding Source: UKRI
- British Heart Foundation [RG/09/012/28096, RG/10/17/28553, PG/07/045/22690, FS/14/51/30879, RG/15/12/31616, RG/13/10/30376, RG/07/010/23676] Funding Source: researchfish
- Medical Research Council [MC_PC_U127561093, G0800270, MC_PC_15018, MR/L003120/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10214, RP-PG-0310-1002, NF-SI-0513-10087, NF-SI-0513-10151, RP-PG-0310-1004] Funding Source: researchfish
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 (similar to 2.7%)(3), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance(4,5). De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations(6,7). 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(8). 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.
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