Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencingTools Sifrim, Alejandro and Hitz, Marc-Phillip and Wilsdon, Anna and Breckpot, Jeroen and Turki, Saeed H Al and Thienpont, Bernard and McRae, Jeremy and Fitzgerald, Tomas W and Singh, Tarjinder and Swaminathan, Ganesh Jawahar and Prigmore, Elena and Rajan, Diana and Abdul-Khaliq, Hashim and Banka, Siddharth and Bauer, Ulrike M.M. and Bentham, Jamie and Berger, Felix and Bhattacharya, Shoumo and Bu'Lock, Frances A. and Canham, Natalie and Colgiu, Irina-Gabriela and Cosgrove, Catherine and Cox, Helen and Daehnert, Ingo and Daly, Allan and Danesh, John and Fryer, Alan and Gewillig, Marc and Hobson, Emma and Hoff, Kirstin and Homfray, Tessa and Kahlert, Anne-Karin and Ketley, Ami and Kramer, Hans-Heiner and Lachlan, Katherine and Lampe, Anne Katrin and Louw, Jacoba J. and Manickara, Ashok Kumar and Manase, Dorin and McCarthy, Karen P. and Metcalfe, Kay and Moore, Carmel and Newbury-Ecob, Ruth and Omer, Seham Osman and Ouwehand, Willem H. and Park, Soo-Mi and Parker, Michael J. and Pickardt, Thomas and Pollard, Martin O. and Robert, Leema and Roberts, David J. and Sambrook, Jennifer and Setchfield, Kerry and Stiller, Brigitte and Thornborough, Christopher and Toka, Okan and Watkins, Hugh and Williams, Denise and Wright, Michael and Mital, Seema and Daubeney, Piers E.F. and Keavney, Bernard and Goodship, Judith and Abu-Sulaiman, Riyadh Mahdi and Klaassen, Sabine and Wright, Caroline F. and Firth, Helen V. and Barrett, Jeffrey C. and Devriendt, Koenraad and FitzPatrick, David R. and Brook, J. David and Hurles, Matthew E. (2016) Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nature Genetics, 48 (9). pp. 1060-1065. ISSN 1546-1718 Full text not available from this repository.AbstractCongenital heart defects (CHDs) have a neonatal incidence of 0.8–1%. 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.
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