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

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dc.contributor Háskóli Íslands (HÍ)
dc.contributor University of Iceland (UI)
dc.contributor.author Björnsson, Þorsteinn
dc.contributor.author Þórólfsdóttir, Rósa B.
dc.contributor.author Sveinbjornsson, Gardar
dc.contributor.author Sulem, Patrick
dc.contributor.author Norðdahl, Guðmundur L.
dc.contributor.author Helgadóttir, Anna
dc.contributor.author Grétarsdóttir, Sólveig
dc.contributor.author Magnusdóttir, Auður
dc.contributor.author Danielsen, Ragnar
dc.contributor.author Sigurðsson, Emil Lárus
dc.contributor.author Adalsteinsdottir, Berglind
dc.contributor.author Gunnarsson, Sverrir I
dc.contributor.author Jonsdottir, Ingileif
dc.contributor.author Arnar, Davíð O.
dc.contributor.author Helgason, Hróðmar
dc.contributor.author Gudbjartsson, Tomas
dc.contributor.author Gudbjartsson, Daniel
dc.contributor.author Thorsteinsdottir, Unnur
dc.contributor.author Holm, Hilma
dc.contributor.author Stefansson, Kari
dc.date.accessioned 2020-01-13T10:48:53Z
dc.date.available 2020-01-13T10:48:53Z
dc.date.issued 2018-03-24
dc.identifier.citation Bjornsson, Thorsteinn et al., 2018. A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta., p.29590334.
dc.identifier.issn 0195-668X
dc.identifier.issn 1522-9645 (eISSN)
dc.identifier.uri https://hdl.handle.net/20.500.11815/1452
dc.description Publisher's version (útgefin grein).
dc.description.abstract 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.
dc.description.sponsorship 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.
dc.format.extent 3243-3249
dc.language.iso en
dc.publisher Oxford University Press (OUP)
dc.relation.ispartofseries European Heart Journal;39(34)
dc.rights info:eu-repo/semantics/openAccess
dc.subject Coarctation of the aorta
dc.subject Genetics
dc.subject MYH6
dc.subject Sarcomere
dc.subject Erfðafræði
dc.subject Hjartasjúkdómar
dc.title A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta
dc.type info:eu-repo/semantics/article
dcterms.license 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
dc.description.version Peer Reviewed
dc.identifier.journal European Heart Journal
dc.identifier.doi 10.1093/eurheartj/ehy142
dc.relation.url http://academic.oup.com/eurheartj/article-pdf/39/34/3243/25694668/ehy142.pdf
dc.contributor.department Faculty of Medicine (UI)
dc.contributor.department Læknadeild (HÍ)
dc.contributor.school Heilbrigðisvísindasvið (HÍ)
dc.contributor.school School of Health Sciences (UI)
dc.contributor.school School of Engineering and Natural Sciences (UI)
dc.contributor.school Verkfræði- og náttúruvísindasvið (HÍ)


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