Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
Sifrim, A; Hitz, M-P; Wilsdon, A; et al.Breckpot, J; Turki, SHA; 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; INTERVAL Study; 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; UK10K Consortium; Abu-Sulaiman, RM; Klaassen, S; Wright, CF; Firth, HV; Barrett, JC; Devriendt, K; FitzPatrick, DR; Brook, JD; Deciphering Developmental Disorders Study; Hurles, ME
Date: 1 August 2016
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 ...
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.
Institute of Medical Education
College of Medicine and Health
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