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

Sifrim A, Hitz MP, Wilsdon A, Breckpot J, Al Turki SH, Thienpont B, Mcrae J, Fitzgerald TW, Singh T, Swaminathan GJ, Prigmore E, Rajan D, Abdul-Khaliq H, Banka S, Bauer UMM, Bentham J, Berger F, Bhattacharya S, Bu'Lock F, Canham N, Colgiu IG, Cosgrove C, Cox H, Daehnert I, Daly A, Danesh J, Fryer A, Gewillig M, Hobson E, Hoff K, Homfray T, Kahlert AK, Ketley A, Kramer HH, Lachlan K, Lampe AK, Louw JJ, Manickara AK, Manase D, Mccarthy KP, Metcalfe K, Moore C, Newbury-Ecob R, Omer SO, Ouwehand WH, Park SM, Parker MJ, Pickardt T, Pollard MO, Robert L, Roberts DJ, Sambrook J, Setchfield K, Stiller B, Thornborough C, Toka O, Watkins H, Williams D, Wright M, Mital S, Daubeney PEF, Keavney B, Goodship J, Abu-Sulaiman RM, Klaassen S, Wright CF, Firth HV, Barrett JC, Devriendt K, Fitzpatrick DR, Brook JD, Hurles ME (2016)

Publication Type: Journal article

Publication year: 2016


Book Volume: 48

Pages Range: 1060-5

Journal Issue: 9

DOI: 10.1038/ng.3627


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.

Additional Organisation(s)

Involved external institutions

Wellcome Trust Sanger Institute - Genome Research Limited GB United Kingdom (GB) University of Nottingham GB United Kingdom (GB) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven BE Belgium (BE) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) BE Belgium (BE) Universität des Saarlandes (UdS) DE Germany (DE) University of Manchester GB United Kingdom (GB) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) DE Germany (DE) Yorkshire Heart Centre GB United Kingdom (GB) University of Oxford GB United Kingdom (GB) Glenfield Hospital GB United Kingdom (GB) London North West Healthcare NHS Trust GB United Kingdom (GB) Birmingham Women's and Children's NHS Foundation Trust GB United Kingdom (GB) Liverpool Women's NHS Foundation Trust GB United Kingdom (GB) Allegan General Hospital US United States (USA) (US) University College London (UCL) GB United Kingdom (GB) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE) Princess Anne Hospital GB United Kingdom (GB) Western General Hospital GB United Kingdom (GB) The Hospital for Sick Children (SickKids) CA Canada (CA) Imperial College London / The Imperial College of Science, Technology and Medicine GB United Kingdom (GB) Central Manchester University Hospitals GB United Kingdom (GB) University of Cambridge GB United Kingdom (GB) University Hospitals Bristol NHS Foundation Trust GB United Kingdom (GB) National Guard Health Affairs SA Saudi Arabia (SA) Cambridge University Hospital GB United Kingdom (GB) Sheffield Children's NHS Foundation Trust GB United Kingdom (GB) Newcastle University GB United Kingdom (GB) Royal Brompton Hospital GB United Kingdom (GB) ​King Abdulaziz Medical City SA Saudi Arabia (SA) University of Edinburgh GB United Kingdom (GB)

How to cite


Sifrim, A., Hitz, M.-P., Wilsdon, A., Breckpot, J., Al Turki, S.H., Thienpont, B.,... Hurles, M.E. (2016). Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nature Genetics, 48(9), 1060-5. https://doi.org/10.1038/ng.3627


Sifrim, Alejandro, et al. "Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing." Nature Genetics 48.9 (2016): 1060-5.

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