Skip to main content

Research Repository

Advanced Search

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

Sifrim, Alejandro; Hitz, Marc-Phillip; Wilsdon, Anna; Breckpot, Jeroen; Turki, Saeed H Al; Thienpont, Bernard; McRae, Jeremy; Fitzgerald, Tomas W; Singh, Tarjinder; Swaminathan, Ganesh Jawahar; Prigmore, Elena; Rajan, Diana; Abdul-Khaliq, Hashim; Banka, Siddharth; Bauer, Ulrike M.M.; Bentham, Jamie; Berger, Felix; Bhattacharya, Shoumo; Bu'Lock, Frances A.; Canham, Natalie; Colgiu, Irina-Gabriela; Cosgrove, Catherine; Cox, Helen; Daehnert, Ingo; Daly, Allan; Danesh, John; Fryer, Alan; Gewillig, Marc; Hobson, Emma; Hoff, Kirstin; Homfray, Tessa; Kahlert, Anne-Karin; Ketley, Ami; Kramer, Hans-Heiner; Lachlan, Katherine; Lampe, Anne Katrin; Louw, Jacoba J.; Manickara, Ashok Kumar; Manase, Dorin; McCarthy, Karen P.; Metcalfe, Kay; Moore, Carmel; Newbury-Ecob, Ruth; Omer, Seham Osman; Ouwehand, Willem H.; Park, Soo-Mi; Parker, Michael J.; Pickardt, Thomas; Pollard, Martin O.; Robert, Leema; Roberts, David J.; Sambrook, Jennifer; Setchfield, Kerry; Stiller, Brigitte; Thornborough, Christopher...

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


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 A. 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

Research Fellow

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

Christopher 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

Professor of Human Genetics

Matthew E. Hurles


Congenital heart defects (CHDs) have a neonatal incidence of 0.8–1%. 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.

Journal Article Type Article
Acceptance Date Jun 24, 2016
Online Publication Date Aug 1, 2016
Publication Date 2016-09
Deposit Date Nov 8, 2016
Publicly Available Date Nov 8, 2016
Journal Nature Genetics
Print ISSN 1061-4036
Electronic ISSN 1546-1718
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 48
Issue 9
Pages 1060-1065
Keywords Clinical Genetics, Congenital Heart Defects, Genetics Research
Public URL
Publisher URL
Related Public URLs
Additional Information Received: 23 December 2015; Accepted: 24 June 2016; First Online: 1 August 2016; : M.E.H. is a cofounder of and holds shares in Congenica Ltd., a genetics diagnostic company.


You might also like

Downloadable Citations