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

Sifrim, Alejandro; Hitz, Marc-Phillip; Wilsdon, Anna; Breckpot, Jeroen; Turki, Saeed H Al; Thienpont, Bernard; McRae, Jeremy; Fitzgerald, Tomas W; Singh, Tarjinder; Swaminathan, Ganesh Jawahar; Prigmore, Elena; Rajan, Diana; Abdul-Khaliq, Hashim; Banka, Siddharth; Bauer, Ulrike M.M.; Bentham, Jamie; Berger, Felix; Bhattacharya, Shoumo; Bu'Lock, Frances A.; Canham, Natalie; Colgiu, Irina-Gabriela; Cosgrove, Catherine; Cox, Helen; Daehnert, Ingo; Daly, Allan; Danesh, John; Fryer, Alan; Gewillig, Marc; Hobson, Emma; Hoff, Kirstin; Homfray, Tessa; Kahlert, Anne-Karin; Ketley, Ami; Kramer, Hans-Heiner; Lachlan, Katherine; Lampe, Anne Katrin; Louw, Jacoba J.; Manickara, Ashok Kumar; Manase, Dorin; McCarthy, Karen P.; Metcalfe, Kay; Moore, Carmel; Newbury-Ecob, Ruth; Omer, Seham Osman; Ouwehand, Willem H.; Park, Soo-Mi; Parker, Michael J.; Pickardt, Thomas; Pollard, Martin O.; Robert, Leema; Roberts, David J.; Sambrook, Jennifer; Setchfield, Kerry; Stiller, Brigitte; Thornborough, Christopher...

Abstract

Congenital 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.

Citation

Sifrim, A., Hitz, M.-P., Wilsdon, A., Breckpot, J., Turki, S. H. A., Thienpont, B., …Hurles, M. E. (2016). Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nature Genetics, 48(9), 1060-1065. https://doi.org/10.1038/ng.3627

• Journal Article Type: Article
• Acceptance Date: Jun 24, 2016
• Online Publication Date: Aug 1, 2016
• Publication Date: 2016-09
• Deposit Date: Nov 8, 2016
• Publicly Available Date: Nov 8, 2016
• Journal: Nature Genetics
• Print ISSN: 1061-4036
• Electronic ISSN: 1546-1718
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 48
• Issue: 9
• Pages: 1060-1065
• DOI: https://doi.org/10.1038/ng.3627
• Keywords: Clinical Genetics, Congenital Heart Defects, Genetics Research
• Public URL: https://nottingham-repository.worktribe.com/output/797962
• Publisher URL: http://www.nature.com/ng/journal/v48/n9/full/ng.3627.html
• Related Public URLs: https://www.research.manchester.ac.uk/portal/en/publications/distinct-genetic-architectures-for-syndromic-and-nonsyndromic-congenital-heart-defects-identified-by-exome-sequencing(01b0a7a8-7160-47fe-9b34-6a7d11b0fa93).html
• Additional Information: Received: 23 December 2015; Accepted: 24 June 2016; First Online: 1 August 2016; : M.E.H. is a cofounder of and holds shares in Congenica Ltd., a genetics diagnostic company.
• Contract Date: Nov 8, 2016