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

Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
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%)3, suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance4, 5. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations6, 7. 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 findings8. 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.
1061-4036
1060-1065
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Sifrim, Alejandro, Hitz, Marc-Phillip, Wilsdon, Anna, Breckpot, Jeroen, Al Turki, Saeed H., 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, 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, Chris, Toka, Okan, Watkins, Hugh, Williams, Denise, Wright, Michael, Mital, Seema, Daubeney, Piers E.F., Keavney, Bernard, Goodship, Judith, Abu-Sulaiman, Riyadh Mahdi, Klaassen, Sabine, Wright, Caroline F., Firth, Helen V., Barrett, Jeffrey C., Devriendt, Koenraad, FitzPatrick, David R., Brook, J. David and Hurles, Matthew E. (2016) Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing. Nature Genetics, 48 (9), 1060-1065. (doi:10.1038/ng.3627).

Record type: Article

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%)3, suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance4, 5. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations6, 7. 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 findings8. 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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Accepted/In Press date: 24 June 2016
e-pub ahead of print date: 1 August 2016
Published date: September 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 402674
URI: http://eprints.soton.ac.uk/id/eprint/402674
ISSN: 1061-4036
PURE UUID: 1b3fff84-bb2a-47be-bd35-e3901d57fd36

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Date deposited: 14 Nov 2016 13:16
Last modified: 06 Oct 2020 22:11

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Contributors

Author: Alejandro Sifrim
Author: Marc-Phillip Hitz
Author: Anna Wilsdon
Author: Jeroen Breckpot
Author: Saeed H. Al Turki
Author: Bernard Thienpont
Author: Jeremy McRae
Author: Tomas W. Fitzgerald
Author: Tarjinder Singh
Author: Ganesh Jawahar Swaminathan
Author: Elena Prigmore
Author: Diana Rajan
Author: Hashim Abdul-Khaliq
Author: Siddharth Banka
Author: Ulrike M.M. Bauer
Author: Jamie Bentham
Author: Felix Berger
Author: Shoumo Bhattacharya
Author: Frances Bu'Lock
Author: Natalie Canham
Author: Irina-Gabriela Colgiu
Author: Catherine Cosgrove
Author: Helen Cox
Author: Ingo Daehnert
Author: Allan Daly
Author: John Danesh
Author: Alan Fryer
Author: Marc Gewillig
Author: Emma Hobson
Author: Kirstin Hoff
Author: Tessa Homfray
Author: Anne-Karin Kahlert
Author: Ami Ketley
Author: Hans-Heiner Kramer
Author: Katherine Lachlan
Author: Anne Katrin Lampe
Author: Jacoba J. Louw
Author: Ashok Kumar Manickara
Author: Dorin Manase
Author: Karen P. McCarthy
Author: Kay Metcalfe
Author: Carmel Moore
Author: Ruth Newbury-Ecob
Author: Seham Osman Omer
Author: Willem H. Ouwehand
Author: Soo-Mi Park
Author: Michael J. Parker
Author: Thomas Pickardt
Author: Martin O. Pollard
Author: Leema Robert
Author: David J. Roberts
Author: Jennifer Sambrook
Author: Kerry Setchfield
Author: Brigitte Stiller
Author: Chris Thornborough
Author: Okan Toka
Author: Hugh Watkins
Author: Denise Williams
Author: Michael Wright
Author: Seema Mital
Author: Piers E.F. Daubeney
Author: Bernard Keavney
Author: Judith Goodship
Author: Riyadh Mahdi Abu-Sulaiman
Author: Sabine Klaassen
Author: Caroline F. Wright
Author: Helen V. Firth
Author: Jeffrey C. Barrett
Author: Koenraad Devriendt
Author: David R. FitzPatrick
Author: J. David Brook
Author: Matthew E. Hurles

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