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Title: Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
Authors: 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
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
the INTERVAL Study
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
the UK10K Consortium
Abu-Sulaiman, Riyadh Mahdi
Klaassen, Sabine
Wright, Caroline F
Firth, Helen V
Barrett, Jeffrey C
Devriendt, Koenraad
FitzPatrick, David R
Brook, J David
the Deciphering Developmental Disorders Study
Hurles, Matthew E #
Issue Date: Sep-2016
Publisher: Nature Publishing Group
Series Title: Nature Genetics vol:48 issue:9
Article number: 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.
ISSN: 1061-4036
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
ESAT - STADIUS, Stadius Centre for Dynamical Systems, Signal Processing and Data Analytics
Laboratory for Genetics of Human Development
Laboratory of Translational Genetics (Vesalius Research Center) (+)
Cardiovascular Developmental Biology
Faculty of health and social work - UC Leuven
× corresponding author
# (joint) last author

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