A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta

• Published in: European Heart Journal
• Main Authors: Björnsson, Þorsteinn, Þórólfsdóttir, Rósa B., Sveinbjornsson, Gardar, sulem, patrick, Norðdahl, Guðmundur L., Helgadóttir, Anna, Grétarsdóttir, Sólveig, Magnusdóttir, Auður, Danielsen, Ragnar, Sigurðsson, Emil Lárus, Adalsteinsdottir, Berglind, Gunnarsson, Sverrir I, Jonsdottir, Ingileif, Arnar, Davíð O., Helgason, Hróðmar, Gudbjartsson, Tomas, Gudbjartsson, Daniel, Thorsteinsdottir, Unnur, Holm, Hilma, Stefansson, Kari
• Other Authors: Faculty of Medicine (UI), Læknadeild (HÍ), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), School of Engineering and Natural Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), Háskóli Íslands (HÍ), University of Iceland (UI)
• Format: Article in Journal/Newspaper
• Language: English
• Published: Oxford University Press (OUP) 2018
• Subjects: Coarctation of the aorta; Genetics; MYH6; Sarcomere; Erfðafræði; Hjartasjúkdómar; Iceland
• Online Access: https://hdl.handle.net/20.500.11815/1452; https://doi.org/10.1093/eurheartj/ehy142

Publisher's version (útgefin grein). 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. 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 lphaheavy 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. 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. © 2018. Published by Oxford University Press on behalf of the European Society of Cardiology. deCODE genetics/Amgen, Inc. The study was approved by the Icelandic Data Protection Authority and the National Bioethics Committee of Iceland. Study approval numbers were VSN-15-053, VSN-15-016, VSN-15-056, VSN-15-058, VSN-15-114, VSN-15-057, and 10-009-S1. Written informed consent was obtained from all study participants. The study complies with the declaration of Helsinki. ...