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

Journal

Book Volume: 48

Pages Range: 1060-5

Journal Issue: 9

DOI: 10.1038/ng.3627

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.

Additional Organisation(s)

Involved external institutions

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

How to cite

APA:

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

MLA:

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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