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

Item Type:Article
Title:Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
Creators Name:Sifrim, A. and Hitz, M.P. and Wilsdon, A. and Breckpot, J. and Turki, S.H.A. and Thienpont, B. and McRae, J. and Fitzgerald, T.W. and Singh, T. and Swaminathan, G.J. and Prigmore, E. and Rajan, D. and Abdul-Khaliq, H. and Banka, S. and Bauer, U.M.M. and Bentham, J. and Berger, F. and Bhattacharya, S. and Bu'Lock, F. and Canham, N. and Colgiu, I.G. and Cosgrove, C. and Cox, H. and Daehnert, I. and Daly, A. and Danesh, J. and Fryer, A. and Gewillig, M. and Hobson, E. and Hoff, K. and Homfray, T. and Kahlert, A.K. and Ketley, A. and Kramer, H.H. and Lachlan, K. and Lampe, A.K. and Louw, J.J. and Manickara, A.K. and Manase, D. and McCarthy, K.P. and Metcalfe, K. and Moore, C. and Newbury-Ecob, R. and Omer, S.O. and Ouwehand, W.H. and Park, S.M. and Parker, M.J. and Pickardt, T. and Pollard, M.O. and Robert, L. and Roberts, D.J. and Sambrook, J. and Setchfield, K. and Stiller, B. and Thornborough, C. and Toka, O. and Watkins, H. and Williams, D. and Wright, M. and Mital, S. and Daubeney, P.E.F. and Keavney, B. and Goodship, J. and Abu-Sulaiman, R.M. and Klaassen, S. and Wright, C.F. and Firth, H.V. and Barrett, J.C. and Devriendt, K. and FitzPatrick, D.R. and Brook, J.D. and Hurles, M.E.
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.
Keywords:Autoantigens, CDC2 Protein Kinase, Congenital Heart Defects, Exome, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Mutation, Protein Conformation, Protein Kinase C, Sequence Deletion, Syndrome
Source:Nature Genetics
ISSN:1061-4036
Publisher:Nature Publishing Group (U.S.A.)
Volume:48
Number:9
Page Range:1060-1065
Date:1 August 2016
Official Publication:https://doi.org/10.1038/ng.3627
PubMed:View item in PubMed

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