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

生物 先证者 外显子组测序 外显率 外显子组 遗传学 兄弟姐妹 基因 突变 表型 心理学 发展心理学
作者
Alejandro Sifrim,Marc‐Phillip Hitz,Anna Wilsdon,Jeroen Breckpot,Saeed H. Al Turki,Bernard Thienpont,Jeremy F. McRae,Tomas Fitzgerald,Tarjinder Singh,G. Jawahar Swaminathan,Elena Prigmore,Diana Rajan,Hashim Abdul‐Khaliq,Siddharth Banka,Ulrike Bauer,Jamie Bentham,Felix Berger,Shoumo Bhattacharya,Frances Bu’Lock,Natalie Canham,Irina-Gabriela Colgiu,Catherine Cosgrove,Helen Cox,Ingo Dähnert,Allan Daly,John Danesh,Alan Fryer,Marc Gewillig,Emma Hobson,Kirstin Hoff,Tessa Homfray,Anne-Karin Kahlert,Ami Ketley,Marc‐Phillip Hitz,Katherine Lachlan,Anne Katrin Lampe,Jacoba Louw,Ashok Kumar Manickara,Dorin Manase,Karen McCarthy,Kay Metcalfe,Carmel Moore,Ruth Newbury‐Ecob,Salah Omer,Willem H. Ouwehand,Soo‐Mi Park,Michael Parker,Thomas Pickardt,Martin Pollard,Leema Robert,David J. Roberts,Jennifer Couper,Kerry Setchfield,Brigitte Stiller,Chris Thornborough,Okan Toka,Hugh Watkins,Denise Williams,Michael Wright,Seema Mital,Piers E.F. Daubeney,Bernard Keavney,Judith A. Goodship,Riyadh Mahdi Abu-Sulaiman,Sabine Klaassen,Caroline F. Wright,Helen V. Firth,Jeffrey C. Barrett,Koenraad Devriendt,David Fitzpatrick,J. David Brook,Matthew E. Hurles
出处
期刊:Nature Genetics [Nature Portfolio]
卷期号:48 (9): 1060-1065 被引量:370
标识
DOI:10.1038/ng.3627
摘要

Matthew Hurles and colleagues report exome sequencing of 1,891 individuals with syndromic or nonsyndromic congenital heart defects (CHD). They found that nonsyndromic CHD patients were enriched for protein-truncating variants in CHD-associated genes inherited from unaffected parents and identified three new syndromic CHD disorders caused by de novo mutations. 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%)3, suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance4,5. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations6,7. 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 findings8. 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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