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

• DOI: 10.1038/ng.3627
• Publication Date: 2016-08-01T17:36:30Z
• Authors: Alejandro Sifrim; ; ; Marc-Phillip Hitz; Anna Wilsdon; Jeroen Breckpot; Saeed H Al Turki; Bernard Thienpont; Jeremy McRae; Tomas W Fitzgerald; Tarjinder Singh; Ganesh Jawahar Sw...; Elena Prigmore; Diana Rajan; Hashim Abdul-Khaliq; Siddharth Banka; Ulrike M M Bauer; Jamie Bentham; Felix Berger; Shoumo Bhattacharya; Frances Bu'Lock; Natalie Canham; Irina-Gabriela Co...; Catherine Cosgrove; Helen Cox; Ingo Daehnert; Allan Daly; John Danesh; Alan Fryer; Marc Gewillig; Emma Hobson; Kirstin Hoff; Tessa Homfray; Anne-Karin Kahlert; Ami Ketley; Hans-Heiner Kramer; Katherine Lachlan; Anne Katrin Lampe; Jacoba J Louw; Ashok Kumar Manic...; Dorin Manase; Karen P McCarthy; Kay Metcalfe; Carmel Moore; Ruth Newbury-Ecob; Seham Osman Omer; Willem H Ouwehand; Soo-Mi Park; Michael J Parker; Thomas Pickardt; Martin O Pollard; Leema Robert; David J Roberts; Jennifer Sambrook; Kerry Setchfield; Brigitte Stiller; Chris Thornborough; Okan Toka; Hugh Watkins; Denise Williams; Michael Wright; Seema Mital; Piers E F Daubeney; Bernard Keavney; Judith Goodship; Riyadh Mahdi Abu-...; Sabine Klaassen; Caroline F Wright; Helen V Firth; Jeffrey C Barrett; Koenraad Devriendt; David R FitzPatrick; J David Brook; Matthew E Hurles
• Keywords: Proband; Exome

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.