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

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


Titill: A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta
Höfundur: Björnsson, Þorsteinn
Þórólfsdóttir, Rósa B.
Sveinbjörnsson, Garðar
Sulem, Patrick   orcid.org/0000-0001-7123-6123
Norðdahl, Guðmundur L.
Helgadóttir, Anna
Grétarsdóttir, Sólveig
Magnusdóttir, Auður
Danielsen, Ragnar
Sigurðsson, Emil L.
... 10 fleiri höfundar Sýna alla höfunda
Útgáfa: 2018-03-24
Tungumál: Enska
Umfang: 3243-3249
Háskóli/Stofnun: Háskóli Íslands (HÍ)
University of Iceland (UI)
Svið: Heilbrigðisvísindasvið (HÍ)
School of Health Sciences (UI)
School of Engineering and Natural Sciences (UI)
Verkfræði- og náttúruvísindasvið (HÍ)
Deild: Faculty of Medicine (UI)
Læknadeild (HÍ)
Birtist í: European Heart Journal;39(34)
ISSN: 0195-668X
1522-9645 (eISSN)
DOI: 10.1093/eurheartj/ehy142
Efnisorð: Coarctation of the aorta; Genetics; MYH6; Sarcomere; Erfðafræði; Hjartasjúkdómar
URI: https://hdl.handle.net/20.500.11815/1452

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Tilvitnun:

Bjornsson, Thorsteinn et al., 2018. A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta., p.29590334.

Útdráttur:

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.

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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