Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing
Authors
- A. Sifrim
- M.P. Hitz
- A. Wilsdon
- J. Breckpot
- S.H.A. Turki
- B. Thienpont
- J. McRae
- T.W. Fitzgerald
- T. Singh
- G.J. Swaminathan
- E. Prigmore
- D. Rajan
- H. Abdul-Khaliq
- S. Banka
- U.M.M. Bauer
- J. Bentham
- F. Berger
- S. Bhattacharya
- F. Bu'Lock
- N. Canham
- I.G. Colgiu
- C. Cosgrove
- H. Cox
- I. Daehnert
- A. Daly
- J. Danesh
- A. Fryer
- M. Gewillig
- E. Hobson
- K. Hoff
- T. Homfray
- A.K. Kahlert
- A. Ketley
- H.H. Kramer
- K. Lachlan
- A.K. Lampe
- J.J. Louw
- A.K. Manickara
- D. Manase
- K.P. McCarthy
- K. Metcalfe
- C. Moore
- R. Newbury-Ecob
- S.O. Omer
- W.H. Ouwehand
- S.M. Park
- M.J. Parker
- T. Pickardt
- M.O. Pollard
- L. Robert
- D.J. Roberts
- J. Sambrook
- K. Setchfield
- B. Stiller
- C. Thornborough
- O. Toka
- H. Watkins
- D. Williams
- M. Wright
- S. Mital
- P.E.F. Daubeney
- B. Keavney
- J. Goodship
- R.M. Abu-Sulaiman
- S. Klaassen
- C.F. Wright
- H.V. Firth
- J.C. Barrett
- K. Devriendt
- D.R. FitzPatrick
- J.D. Brook
- M.E. Hurles
Journal
- Nature Genetics
Citation
- Nat Genet 48 (9): 1060-1065
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.