A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta.
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download Coarctation of the aorta (CoA) accounts for 4-8% of congenital heart defects (CHDs) and confers substantial morbidity...
Published in: | European Heart Journal |
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Main Authors: | , , , , , , , , , , , , , , , , , , , |
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Format: | Article in Journal/Newspaper |
Language: | English |
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Oxford University Press
2018
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Online Access: | http://hdl.handle.net/2336/620716 https://doi.org/10.1093/eurheartj/ehy142 |
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Open Polar |
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Hirsla - Landspítali University Hospital research archive |
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English |
topic |
Hjartasjúkdómar Arfgengi Gen Æðasjúkdómar Aortic Coarctation Heart Diseases Genes Heart Defects Congenital Genome-Wide Association Study |
spellingShingle |
Hjartasjúkdómar Arfgengi Gen Æðasjúkdómar Aortic Coarctation Heart Diseases Genes Heart Defects Congenital Genome-Wide Association Study Bjornsson, Thorsteinn Thorolfsdottir, Rosa B Sveinbjornsson, Gardar Sulem, Patrick Norddahl, Gudmundur L Helgadottir, Anna Gretarsdottir, Solveig Magnusdottir, Audur Danielsen, Ragnar Sigurdsson, Emil L Adalsteinsdottir, Berglind Gunnarsson, Sverrir I Jonsdottir, Ingileif Arnar, David O Helgason, Hrodmar Gudbjartsson, Tomas Gudbjartsson, Daniel F Thorsteinsdottir, Unnur Holm, Hilma Stefansson, Kari A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta. |
topic_facet |
Hjartasjúkdómar Arfgengi Gen Æðasjúkdómar Aortic Coarctation Heart Diseases Genes Heart Defects Congenital Genome-Wide Association Study |
description |
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download 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. 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. 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. deCODE genetics/Amgen, Inc. |
author2 |
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 Family Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland. 4 Department of Development, Primary Health Care of the Capital Area, Alfabakki 16, Reykjavik, Iceland. 5 Department of Cardiology, Haukeland University Hospital, Jonas Lies vei 83, Bergen, Norway. 6 Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland. 7 Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, 600 Highland Ave, Madison, WI, USA. 8 Department of Immunology, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland. 9 Children's Hospital, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland. 10 Department of Cardiothoracic Surgery, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland. 11 School of Engineering and Natural Sciences, University of Iceland, Hjardarhagi 4, Reykjavik, Iceland. |
format |
Article in Journal/Newspaper |
author |
Bjornsson, Thorsteinn Thorolfsdottir, Rosa B Sveinbjornsson, Gardar Sulem, Patrick Norddahl, Gudmundur L Helgadottir, Anna Gretarsdottir, Solveig Magnusdottir, Audur Danielsen, Ragnar Sigurdsson, Emil L Adalsteinsdottir, Berglind Gunnarsson, Sverrir I Jonsdottir, Ingileif Arnar, David O Helgason, Hrodmar Gudbjartsson, Tomas Gudbjartsson, Daniel F Thorsteinsdottir, Unnur Holm, Hilma Stefansson, Kari |
author_facet |
Bjornsson, Thorsteinn Thorolfsdottir, Rosa B Sveinbjornsson, Gardar Sulem, Patrick Norddahl, Gudmundur L Helgadottir, Anna Gretarsdottir, Solveig Magnusdottir, Audur Danielsen, Ragnar Sigurdsson, Emil L Adalsteinsdottir, Berglind Gunnarsson, Sverrir I Jonsdottir, Ingileif Arnar, David O Helgason, Hrodmar Gudbjartsson, Tomas Gudbjartsson, Daniel F Thorsteinsdottir, Unnur Holm, Hilma Stefansson, Kari |
author_sort |
Bjornsson, Thorsteinn |
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 |
publishDate |
2018 |
url |
http://hdl.handle.net/2336/620716 https://doi.org/10.1093/eurheartj/ehy142 |
genre |
Iceland |
genre_facet |
Iceland |
op_source |
European heart journal |
op_relation |
https://academic.oup.com/eurheartj/article/39/34/3243/4953519 A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta. 2018, 39(34):3243-3249 European heart journal 1522-9645 29590334 doi:10.1093/eurheartj/ehy142 http://hdl.handle.net/2336/620716 European heart journal |
op_rights |
Open Access - Opinn aðgangur |
op_doi |
https://doi.org/10.1093/eurheartj/ehy142 |
container_title |
European Heart Journal |
container_volume |
39 |
container_issue |
34 |
container_start_page |
3243 |
op_container_end_page |
3249 |
_version_ |
1766041936308731904 |
spelling |
ftlandspitaliuni:oai:www.hirsla.lsh.is:2336/620716 2023-05-15T16:51:49+02:00 A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta. Bjornsson, Thorsteinn Thorolfsdottir, Rosa B Sveinbjornsson, Gardar Sulem, Patrick Norddahl, Gudmundur L Helgadottir, Anna Gretarsdottir, Solveig Magnusdottir, Audur Danielsen, Ragnar Sigurdsson, Emil L Adalsteinsdottir, Berglind Gunnarsson, Sverrir I Jonsdottir, Ingileif Arnar, David O Helgason, Hrodmar Gudbjartsson, Tomas Gudbjartsson, Daniel F Thorsteinsdottir, Unnur Holm, Hilma Stefansson, Kari 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 Family Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland. 4 Department of Development, Primary Health Care of the Capital Area, Alfabakki 16, Reykjavik, Iceland. 5 Department of Cardiology, Haukeland University Hospital, Jonas Lies vei 83, Bergen, Norway. 6 Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, Reykjavik, Iceland. 7 Division of Cardiovascular Medicine, Department of Medicine, University of Wisconsin, 600 Highland Ave, Madison, WI, USA. 8 Department of Immunology, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland. 9 Children's Hospital, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland. 10 Department of Cardiothoracic Surgery, Landspitali-The National University Hospital of Iceland, Hringbraut, Reykjavik, Iceland. 11 School of Engineering and Natural Sciences, University of Iceland, Hjardarhagi 4, Reykjavik, Iceland. 2018-10 http://hdl.handle.net/2336/620716 https://doi.org/10.1093/eurheartj/ehy142 en eng Oxford University Press https://academic.oup.com/eurheartj/article/39/34/3243/4953519 A rare missense mutation in MYH6 associates with non-syndromic coarctation of the aorta. 2018, 39(34):3243-3249 European heart journal 1522-9645 29590334 doi:10.1093/eurheartj/ehy142 http://hdl.handle.net/2336/620716 European heart journal Open Access - Opinn aðgangur European heart journal Hjartasjúkdómar Arfgengi Gen Æðasjúkdómar Aortic Coarctation Heart Diseases Genes Heart Defects Congenital Genome-Wide Association Study Article 2018 ftlandspitaliuni https://doi.org/10.1093/eurheartj/ehy142 2022-05-29T08:22:22Z To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Download 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. 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. 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. deCODE genetics/Amgen, Inc. Article in Journal/Newspaper Iceland Hirsla - Landspítali University Hospital research archive European Heart Journal 39 34 3243 3249 |