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

Bjornsson, T.; Thorolfsdottir, R. B.; Sveinbjornsson, G.; Sulem, P.; Norddahl, G. L.; Helgadottir, A.; Gretarsdottir, S.; Magnusdottir, A.; Danielsen, R.; Sigurdsson, E. L.; Adalsteinsdottir, B.; Gunnarsson, S. I.; Jonsdottir, I.; Arnar, D. O.; Helgason, H.; Gudbjartsson, T.; Gudbjartsson, D. F.; Thorsteinsdottir, U.; Holm, H.; Stefansson, K.

doi:10.1101/180794

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bioRxiv · 10.1101/180794

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

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Abstract

Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and carries substantial morbidity despite treatment1. 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)2. 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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Bjornsson, T., Thorolfsdottir, R. B., Sveinbjornsson, G., Sulem, P., Norddahl, G. L., Helgadottir, A., Gretarsdottir, S., Magnusdottir, A., Danielsen, R., Sigurdsson, E. L., Adalsteinsdottir, B., Gunnarsson, S. I., Jonsdottir, I., Arnar, D. O., Helgason, H., Gudbjartsson, T., Gudbjartsson, D. F., Thorsteinsdottir, U., Holm, H., Stefansson, K.. 2017-08-29. A rare missense mutation in MYH6 confers high risk of coarctation of the aorta. https://doi.org/10.1101/180794

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