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

INTERVAL Study, Alejandro Sifrim, Marc-Phillip Hitz, Anna Wilsdon, Jeroen Breckpot, Saeed H Al Turki, Bernard Thienpont, Jeremy McRae, Tomas W Fitzgerald, Tarjinder Singh, Ganesh Jawahar Swaminathan, Elena Prigmore, Diana Rajan, Hashim Abdul-Khaliq, Siddharth Banka, Ulrike M M Bauer, Jamie Bentham, Felix Berger, Shoumo Bhattacharya, Frances Bu'LockNatalie Canham, Irina-Gabriela Colgiu, 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 Manickara, 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, David R FitzPatrick

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1060-5
Number of pages6
JournalNature Genetics
Volume48
Issue number9
Early online date1 Aug 2016
DOIs
Publication statusPublished - Sep 2016

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