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

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Title: Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
Author(s): Sifrim, A
Hitz, M-P
Wilsdon, A
Breckpot, J
Al Turki, SH
Thienpont, B
McRae, J
Fitzgerald, TW
Singh, T
Swaminathan, GJ
Prigmore, E
Rajan, D
Abdul-Khaliq, H
Banka, S
Bauer, UMM
Bentham, J
Berger, F
Bhattacharya, S
Bu'Lock, F
Canham, N
Colgiu, I-G
Cosgrove, C
Cox, H
Daehnert, I
Daly, A
Danesh, J
Fryer, A
Gewillig, M
Hobson, E
Hoff, K
Homfray, T
Kahlert, A-K
Ketley, A
Kramer, H-H
Lachlan, K
Lampe, AK
Louw, JJ
Manickara, AK
Manase, D
McCarthy, KP
Metcalfe, K
Moore, C
Newbury-Ecob, R
Omer, SO
Ouwehand, WH
Park, S-M
Parker, MJ
Pickardt, T
Pollard, MO
Robert, L
Roberts, DJ
Sambrook, J
Setchfield, K
Stiller, B
Thornborough, C
Toka, O
Watkins, H
Williams, D
Wright, M
Mital, S
Daubeney, PEF
Keavney, B
Goodship, J
Abu-Sulaiman, RM
Klaassen, S
Wright, CF
Firth, HV
Barrett, JC
Devriendt, K
FitzPatrick, DR
Brook, JD
Hurles, ME
Item 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.
Publication Date: 1-Aug-2016
Date of Acceptance: 24-Jun-2016
URI: http://hdl.handle.net/10044/1/42666
DOI: https://dx.doi.org/10.1038/ng.3627
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.
Keywords: 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
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine
Epidemiology, Public Health and Primary Care



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