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

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; Leema Robert; David J Roberts; Jennifer Sambrook; Kerry Setchfield; Brigitte Stiller; Chris Thornborough; Okan Toka; Hugh Watkins; Denise Williams; Michael Wright; Seema Mital; Piers E F Daubeney; Bernard Keavney; Judith Goodship; Riyadh Mahdi Abu-Sulaiman; Sabine Klaassen; Caroline F Wright; Helen V Firth; Jeffrey C Barrett; Koenraad Devriendt; David R FitzPatrick; J David Brook; Matthew E Hurles; INTERVAL Study

doi:10.1038/ng.3627

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

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

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, …

Nature genetics, Vol.48(9), pp.1060-1065

01/09/2016

DOI: https://doi.org/10.1038/ng.3627

PMID: 27479907

Abstract

Autoantigens - genetics

CDC2 Protein Kinase - chemistry

CDC2 Protein Kinase - genetics

Exome - genetics

Female

Heart Defects, Congenital - genetics

Humans

Male

Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics

Mutation - genetics

Protein Conformation

Protein Kinase C - genetics

Sequence Deletion

Syndrome

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.

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Title: Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
Creators - without role: Alejandro Sifrim - Wellcome Sanger Institute
Marc-Phillip Hitz - German Center for Cardiovascular Research (DZHK), Berlin, Germany
Anna Wilsdon - University of Nottingham
Jeroen Breckpot - Center for Human Genetics
Saeed H Al Turki - Harvard Medical School
Bernard Thienpont - KU Leuven
Jeremy McRae - Wellcome Sanger Institute
Tomas W Fitzgerald - Wellcome Sanger Institute
Tarjinder Singh - Wellcome Sanger Institute
Ganesh Jawahar Swaminathan - Wellcome Sanger Institute
Elena Prigmore - Wellcome Sanger Institute
Diana Rajan - Wellcome Sanger Institute
Hashim Abdul-Khaliq - Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany
Siddharth Banka - University of Manchester
Ulrike M M Bauer - Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany
Jamie Bentham - Department of Paediatric Cardiology, Yorkshire Heart Centre, Leeds, UK
Felix Berger - Charité - Universitätsmedizin Berlin
Shoumo Bhattacharya - University of Oxford
Frances Bu'Lock - Glenfield Hospital
Natalie Canham - London North West Healthcare NHS Trust
Irina-Gabriela Colgiu - Wellcome Sanger Institute
Catherine Cosgrove - University of Oxford
Helen Cox - Birmingham Women's Hospital
Ingo Daehnert - Department of Pediatric Cardiology, Heart Center, University of Leipzig, Leipzig, Germany
Allan Daly - Wellcome Sanger Institute
John Danesh - University of Cambridge
Alan Fryer - Department of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK
Marc Gewillig - Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium
Emma Hobson - Leeds Teaching Hospitals NHS Trust
Kirstin Hoff - German Center for Cardiovascular Research (DZHK), Berlin, Germany
Tessa Homfray - University of London
Anne-Karin Kahlert - Faculty
Ami Ketley - University of Nottingham
Hans-Heiner Kramer - Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany
Katherine Lachlan - University of Southampton
Anne Katrin Lampe - South East of Scotland Clinical Genetic Service, IGMM North, Western General Hospital, Edinburgh, UK
Jacoba J Louw - Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium
Ashok Kumar Manickara - Hospital for Sick Children, Toronto, Ontario, Canada
Dorin Manase - Hospital for Sick Children, Toronto, Ontario, Canada
Karen P McCarthy - Royal Brompton Hospital
Kay Metcalfe - Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
Carmel Moore - University of Cambridge
Ruth Newbury-Ecob - Department of Clinical Genetics, St Michael's Hospital, Bristol, UK
Seham Osman Omer - King Abdulaziz Medical City
Willem H Ouwehand - NHS Blood and Transplant
Soo-Mi Park - Cambridge University Hospitals NHS Foundation Trust
Michael J Parker - Sheffield Children's Hospital
Thomas Pickardt - Competence Network for Congenital Heart Defects, National Register for Congenital Heart Defects, DZHK, Berlin, Germany
Martin O Pollard - Wellcome Sanger Institute
Leema Robert - Guy's and St Thomas' NHS Foundation Trust
David J Roberts - University of Oxford
Jennifer Sambrook - University of Cambridge
Kerry Setchfield - University of Nottingham
Brigitte Stiller - University of Freiburg
Chris Thornborough - Glenfield Hospital
Okan Toka - Friedrich Alexander Universität Erlangen-Nürnberg (FAU), Department of Pediatric Cardiology, Erlangen, Germany
Hugh Watkins - University of Oxford
Denise Williams - Birmingham Women's Hospital
Michael Wright - Newcastle upon Tyne Hospitals NHS Foundation Trust
Seema Mital - Hospital for Sick Children, Toronto, Ontario, Canada
Piers E F Daubeney - Imperial College London
Bernard Keavney - University of Manchester
Judith Goodship - Newcastle University
Riyadh Mahdi Abu-Sulaiman - King Abdullah International Medical Research Center
Sabine Klaassen - Charité - Universitätsmedizin Berlin
Caroline F Wright - Wellcome Sanger Institute
Helen V Firth - Cambridge University Hospitals NHS Foundation Trust
Jeffrey C Barrett - Wellcome Sanger Institute
Koenraad Devriendt - Center for Human Genetics
David R FitzPatrick - University of Edinburgh
J David Brook - University of Nottingham
Matthew E Hurles - Wellcome Sanger Institute
INTERVAL Study
Publication Details: Nature genetics, Vol.48(9), pp.1060-1065
Grant note: Wellcome Trust 091986 / Wellcome Trust RP-PG-0310-1004 / Department of Health FS/14/51/30879 / British Heart Foundation CIHR RG/13/13/30194 / British Heart Foundation RG/15/12/31616 / British Heart Foundation RG/13/10/30376 / British Heart Foundation MR/L003120/1 / Medical Research Council RG/10/17/28553 / British Heart Foundation G0800270 / Medical Research Council RG/07/010/23676 / British Heart Foundation RP-PG-0310-1002 / Department of Health RG/09/012/28096 / British Heart Foundation PG/07/045/22690 / British Heart Foundation MC_PC_U127561093 / Medical Research Council WT098051 / Wellcome Trust MC_PC_15018 / Medical Research Council 098051 / Wellcome Trust SP/09/002 / British Heart Foundation
Identifiers: 9921321808331
Academic Unit: King Abdulaziz University; King Saud Bin Abdulaziz University for Health Sciences
Language: English
Resource Type: Journal article