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A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta.
- Source :
-
European heart journal [Eur Heart J] 2018 Sep 07; Vol. 39 (34), pp. 3243-3249. - Publication Year :
- 2018
-
Abstract
- Aims: Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and confers substantial morbidity despite treatment. It is increasingly recognized as a highly heritable condition. The aim of the study was to search for sequence variants that affect the risk of CoA.<br />Methods and Results: We performed a genome-wide association study of CoA among Icelanders (120 cases and 355 166 controls) based on imputed variants identified through whole-genome sequencing. We found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp in MYH6 (odds ratio = 44.2, P = 5.0 × 10-22), encoding the alpha-heavy chain subunit of cardiac myosin, an essential sarcomere protein. Approximately 20% of individuals with CoA in Iceland carry this mutation. We show that p.Arg721Trp also associates with other CHDs, in particular bicuspid aortic valve. We have previously reported broad effects of p.Arg721Trp on cardiac electrical function and strong association with sick sinus syndrome and atrial fibrillation.<br />Conclusion: Through a population approach, we found that a rare missense mutation p.Arg721Trp in the sarcomere gene MYH6 has a strong effect on the risk of CoA and explains a substantial fraction of the Icelanders with CoA. This is the first mutation associated with non-familial or sporadic form of CoA at a population level. The p.Arg721Trp in MYH6 causes a cardiac syndrome with highly variable expressivity and emphasizes the importance of sarcomere integrity for cardiac development and function.
- Subjects :
- Adolescent
Adult
Aortic Coarctation metabolism
Asymptomatic Diseases
Cardiac Myosins metabolism
Child
Child, Preschool
DNA Mutational Analysis
Female
Humans
Infant
Infant, Newborn
Male
Myosin Heavy Chains metabolism
Pedigree
Retrospective Studies
Young Adult
Aortic Coarctation genetics
Cardiac Myosins genetics
DNA genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Mutation, Missense
Myosin Heavy Chains genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1522-9645
- Volume :
- 39
- Issue :
- 34
- Database :
- MEDLINE
- Journal :
- European heart journal
- Publication Type :
- Academic Journal
- Accession number :
- 29590334
- Full Text :
- https://doi.org/10.1093/eurheartj/ehy142