Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada
Aims Autosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes ident...
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fthighwire:oai:open-archive.highwire.org:ehj:34/13/1002 2023-05-15T17:21:00+02:00 Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada Haywood, Annika F.M. Merner, Nancy D. Hodgkinson, Kathy A. Houston, Jim Syrris, Petros Booth, Valerie Connors, Sean Pantazis, Antonios Quarta, Giovanni Elliott, Perry McKenna, William Young, Terry-Lynn 2013-04-01 00:00:00.0 text/html http://eurheartj.oxfordjournals.org/cgi/content/short/34/13/1002 https://doi.org/10.1093/eurheartj/ehs383 en eng Oxford University Press http://eurheartj.oxfordjournals.org/cgi/content/short/34/13/1002 http://dx.doi.org/10.1093/eurheartj/ehs383 Copyright (C) 2013, European Society of Cardiology Heart failure/cardiomyopathy TEXT 2013 fthighwire https://doi.org/10.1093/eurheartj/ehs383 2016-11-16T17:14:16Z Aims Autosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland. Methods and results Bidirectional sequencing of TMEM43 including intron–exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry. Conclusion Although the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation. Text Newfoundland HighWire Press (Stanford University) Canada European Heart Journal 34 13 1002 1011 |
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Open Polar |
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HighWire Press (Stanford University) |
op_collection_id |
fthighwire |
language |
English |
topic |
Heart failure/cardiomyopathy |
spellingShingle |
Heart failure/cardiomyopathy Haywood, Annika F.M. Merner, Nancy D. Hodgkinson, Kathy A. Houston, Jim Syrris, Petros Booth, Valerie Connors, Sean Pantazis, Antonios Quarta, Giovanni Elliott, Perry McKenna, William Young, Terry-Lynn Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada |
topic_facet |
Heart failure/cardiomyopathy |
description |
Aims Autosomal dominant arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) (in the group of arrhythmogenic cardiomyopathies) is a common cause of sudden cardiac death in young adults. It is both clinically and genetically heterogeneous, with 12 loci (ARVC/D1-12) and eight genes identified, the majority of which encode structural proteins of cardiac desmosomes. The most recent gene identified, TMEM43, causes disease due to a missense mutation in a non-desmosomal gene (p.S358L) in 15 extended families from Newfoundland, Canada. To determine whether mutations in TMEM43 cause ARVC/D and arrhythmogenic cardiomyopathy in other populations, we fully re-sequenced TMEM43 on 143 ARVC/D probands (families) from the UK and 55 probands (from 55 families) from Newfoundland. Methods and results Bidirectional sequencing of TMEM43 including intron–exon boundaries revealed 33 variants, the majority located in non-coding regions of TMEM43. For the purpose of validation, families of probands with rare, potentially deleterious coding variants were subjected to clinical and molecular follow-up. Three missense variants of uncertain significance (p.R28W, p.E142K, p.R312W) were located in highly conserved regions of the TMEM43 protein. One variant (p.R312W) also co-segregated with relatives showing clinical signs of disease. Genotyping and expansion of the disease-associated haplotype in subjects with the p.R312W variant from Newfoundland, Canada, and the UK suggest common ancestry. Conclusion Although the p.R312W variant was found in controls (3/378), identification of an ancestral disease p R312W haplotype suggests that the p.R312W variant is a pathogenic founder mutation. |
format |
Text |
author |
Haywood, Annika F.M. Merner, Nancy D. Hodgkinson, Kathy A. Houston, Jim Syrris, Petros Booth, Valerie Connors, Sean Pantazis, Antonios Quarta, Giovanni Elliott, Perry McKenna, William Young, Terry-Lynn |
author_facet |
Haywood, Annika F.M. Merner, Nancy D. Hodgkinson, Kathy A. Houston, Jim Syrris, Petros Booth, Valerie Connors, Sean Pantazis, Antonios Quarta, Giovanni Elliott, Perry McKenna, William Young, Terry-Lynn |
author_sort |
Haywood, Annika F.M. |
title |
Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada |
title_short |
Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada |
title_full |
Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada |
title_fullStr |
Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada |
title_full_unstemmed |
Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada |
title_sort |
recurrent missense mutations in tmem43 (arvd5) due to founder effects cause arrhythmogenic cardiomyopathies in the uk and canada |
publisher |
Oxford University Press |
publishDate |
2013 |
url |
http://eurheartj.oxfordjournals.org/cgi/content/short/34/13/1002 https://doi.org/10.1093/eurheartj/ehs383 |
geographic |
Canada |
geographic_facet |
Canada |
genre |
Newfoundland |
genre_facet |
Newfoundland |
op_relation |
http://eurheartj.oxfordjournals.org/cgi/content/short/34/13/1002 http://dx.doi.org/10.1093/eurheartj/ehs383 |
op_rights |
Copyright (C) 2013, European Society of Cardiology |
op_doi |
https://doi.org/10.1093/eurheartj/ehs383 |
container_title |
European Heart Journal |
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34 |
container_issue |
13 |
container_start_page |
1002 |
op_container_end_page |
1011 |
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1766103494627950592 |