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

Research output: Contribution to journalArticlepeer-review

  • 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 Swaminathan
  • 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 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
  • Bernard Keavney
  • INTERVAL Study


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.

Bibliographical metadata

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

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