Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
File(s)
Accepted version
Author(s)
Type
Journal Article
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%)3, suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance4, 5. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations6, 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 findings8. 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.
Date Issued
2016-08-01
Date Acceptance
2016-06-24
Citation
Nature Genetics, 2016, 48 (9), pp.1060-1065
ISSN
1061-4036
Publisher
Nature Publishing Group
Start Page
1060
End Page
1065
Journal / Book Title
Nature Genetics
Volume
48
Issue
9
Copyright Statement
© 2016 Nature America, Inc. All rights reserved.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000382398800018&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
DE-NOVO MUTATIONS
DISEASE
RECURRENCE
DISCOVERY
FRAMEWORK
GENOTYPE
FAMILIES
INTERVAL Study
UK10K Consortium
Deciphering Developmental Disorders Study
Developmental Biology
11 Medical And Health Sciences
06 Biological Sciences
Publication Status
Published