A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta
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 varia...
Published in: | European Heart Journal |
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Language: | English |
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Oxford University Press (OUP)
2018
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Online Access: | https://hdl.handle.net/20.500.11815/1452 https://doi.org/10.1093/eurheartj/ehy142 |
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ftopinvisindi:oai:opinvisindi.is:20.500.11815/1452 2023-05-15T16:49:04+02:00 A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta 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 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) 2018-03-24 3243-3249 https://hdl.handle.net/20.500.11815/1452 https://doi.org/10.1093/eurheartj/ehy142 en eng Oxford University Press (OUP) European Heart Journal;39(34) http://academic.oup.com/eurheartj/article-pdf/39/34/3243/25694668/ehy142.pdf Bjornsson, Thorsteinn et al., 2018. A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta., p.29590334. 0195-668X 1522-9645 (eISSN) https://hdl.handle.net/20.500.11815/1452 European Heart Journal doi:10.1093/eurheartj/ehy142 info:eu-repo/semantics/openAccess Coarctation of the aorta Genetics MYH6 Sarcomere Erfðafræði Hjartasjúkdómar info:eu-repo/semantics/article 2018 ftopinvisindi https://doi.org/20.500.11815/1452 https://doi.org/10.1093/eurheartj/ehy142 2022-11-18T06:51:50Z 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. ... Article in Journal/Newspaper Iceland Opin vísindi (Iceland) European Heart Journal 39 34 3243 3249 |
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Opin vísindi (Iceland) |
op_collection_id |
ftopinvisindi |
language |
English |
topic |
Coarctation of the aorta Genetics MYH6 Sarcomere Erfðafræði Hjartasjúkdómar |
spellingShingle |
Coarctation of the aorta Genetics MYH6 Sarcomere Erfðafræði Hjartasjúkdómar 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 A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta |
topic_facet |
Coarctation of the aorta Genetics MYH6 Sarcomere Erfðafræði Hjartasjúkdómar |
description |
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. ... |
author2 |
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 |
author |
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 |
author_facet |
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 |
author_sort |
Björnsson, Þorsteinn |
title |
A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta |
title_short |
A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta |
title_full |
A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta |
title_fullStr |
A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta |
title_full_unstemmed |
A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta |
title_sort |
rare missense mutation in myh6 associates with non-syndromic coarctation of the aorta |
publisher |
Oxford University Press (OUP) |
publishDate |
2018 |
url |
https://hdl.handle.net/20.500.11815/1452 https://doi.org/10.1093/eurheartj/ehy142 |
genre |
Iceland |
genre_facet |
Iceland |
op_relation |
European Heart Journal;39(34) http://academic.oup.com/eurheartj/article-pdf/39/34/3243/25694668/ehy142.pdf Bjornsson, Thorsteinn et al., 2018. A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta., p.29590334. 0195-668X 1522-9645 (eISSN) https://hdl.handle.net/20.500.11815/1452 European Heart Journal doi:10.1093/eurheartj/ehy142 |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/20.500.11815/1452 https://doi.org/10.1093/eurheartj/ehy142 |
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European Heart Journal |
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39 |
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34 |
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3249 |
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1766039128496930816 |