Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.
Nat Genet
; 48(9): 1060-5, 2016 09.
Article
in En
| MEDLINE
| ID: mdl-27479907
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 (â¼2.7%), 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Autoantigens
/
Protein Kinase C
/
CDC2 Protein Kinase
/
Mi-2 Nucleosome Remodeling and Deacetylase Complex
/
Heart Defects, Congenital
/
Mutation
Type of study:
Prognostic_studies
Limits:
Female
/
Humans
/
Male
Language:
En
Journal:
Nat Genet
Journal subject:
GENETICA MEDICA
Year:
2016
Document type:
Article
Affiliation country:
Reino Unido