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A rare missense mutation in MYH6 confers high risk of coarctation of the aorta

By Thorsteinn Bjornsson, Rosa B. Thorolfsdottir, Gardar Sveinbjornsson, Patrick Sulem, Gudmundur L. Norddahl, Anna Helgadottir, Solveig Gretarsdottir, Audur Magnusdottir, Ragnar Danielsen, Emil L. Sigurdsson, Berglind Adalsteinsdottir, Sverrir I. Gunnarsson, Ingileif Jonsdottir, David O. Arnar, Hrodmar Helgason, Tomas Gudbjartsson, Daniel F. Gudbjartsson, Unnur Thorsteinsdottir, Hilma Holm, Kari Stefansson

Posted 29 Aug 2017
bioRxiv DOI: 10.1101/180794 (published DOI: 10.1093/eurheartj/ehy142)

Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and carries substantial morbidity despite treatment. We performed a genome-wide association study (GWAS) of CoA among 120 Icelandic cases and 355,166 controls and found association with a rare (frequency = 0.34%) missense mutation p.Arg721Trp in MYH6 (odds ratio (OR) = 44.2, P = 5.0x10-22), encoding an essential sarcomere protein. Approximately 20% of CoA cases in Iceland carry p.Arg721Trp. This is the first mutation associated with non-familial or sporadic CoA at a population level. P.Arg721Trp also associates with risk of bicuspid aortic valve (BAV) and other CHDs and has been reported to have a broad effect on cardiac electrical function and to associate strongly with sick sinus syndrome (SSS) and atrial fibrillation (AF). These findings suggest that p.Arg721Trp in MYH6 causes a cardiac syndrome with highly variable expressivity, and emphasize the major importance of sarcomere integrity for cardiac development and function.

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