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

Eur. Heart J.2018 Sep 07;39(34):3243-3249
Thorsteinn Bjornsson 1 , Rosa B Thorolfsdottir 1 , Gardar Sveinbjornsson 1 , Patrick Sulem 1 , Gudmundur L Norddahl 1 , Anna Helgadottir 1 , Solveig Gretarsdottir 1 , Audur Magnusdottir 1 , Ragnar Danielsen 2 , Emil L Sigurdsson 3 , Berglind Adalsteinsdottir 4 , Sverrir I Gunnarsson 5 , Ingileif Jonsdottir 6 , David O Arnar 4 , Hrodmar Helgason 7 , Tomas Gudbjartsson 8 , Daniel F Gudbjartsson 9 , Unnur Thorsteinsdottir 4 , Hilma Holm 1 , Kari Stefansson 4
Thorsteinn Bjornsson 1 , Rosa B Thorolfsdottir 1 , Gardar Sveinbjornsson 1 , Patrick Sulem 1 , Gudmundur L Norddahl 1 , Anna Helgadottir 1 , Solveig Gretarsdottir 1 , Audur Magnusdottir 1 , Ragnar Danielsen 2 , Emil L Sigurdsson 3 , Berglind Adalsteinsdottir 4 , Sverrir I Gunnarsson 5 , Ingileif Jonsdottir 6 , David O Arnar 4 , Hrodmar Helgason 7 , Tomas Gudbjartsson 8 , Daniel F Gudbjartsson 9 , Unnur Thorsteinsdottir 4 , Hilma Holm 1 , Kari Stefansson 4
+ et al

[No authors listed]

Author information
  • 1 deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik, Iceland.
  • 2 Department of Medicine, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland.
  • 3 Department of Development, Primary Health Care of the Capital Area, Alfabakki 16, Reykjavik, Iceland.
  • 4 Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland.
  • 5 Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, 600 Highland Ave, Madison, WI, USA.
  • 6 Department of Immunology, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland.
  • 7 Children's Hospital, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland.
  • 8 Department of Cardiothoracic Surgery, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland.
  • 9 School of Engineering and Natural Sciences, University of Iceland, Hjardarhagi 4, Reykjavik, Iceland.

摘要

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 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. 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.

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