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

Journal article


Publication Details

Author(s): 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
Journal: Nature Genetics
Publication year: 2016
Volume: 48
Journal issue: 9
Pages range: 1060-5
ISSN: 1061-4036


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
Kinderherzchirurgische Abteilung in der Herzchirurgischen Klinik


External institutions with authors

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


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://dx.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.

BibTeX: 

Last updated on 2018-09-10 at 07:18