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Abstract / Description of output
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.
Original language | English |
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Pages (from-to) | 1060-5 |
Number of pages | 6 |
Journal | Nature Genetics |
Volume | 48 |
Issue number | 9 |
Early online date | 1 Aug 2016 |
DOIs | |
Publication status | Published - Sept 2016 |
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Dive into the research topics of 'Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing'. Together they form a unique fingerprint.Projects
- 1 Finished
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HGU Core Award Apr 12 - MAr 18
Hastie, N., Adams, I., Baldock, R., Bickmore, W., Caceres, J., Dorin, J., FitzPatrick, D., Haley, C., Hill, B., Jackson, I., Jackson, A., Kudla, G., Meehan, R. & Patton, E.
1/04/12 → 31/03/18
Project: Research