Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada

Handle URI:
http://hdl.handle.net/10754/594089
Title:
Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada
Authors:
Haywood, Annika; 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
Abstract:
AimsAutosomal 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 resultsBidirectional 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.ConclusionAlthough 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. © 2012 The Author.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Computational Bioscience Research Center (CBRC)
Citation:
Haywood AFM, Merner ND, Hodgkinson KA, Houston J, Syrris P, et al. (2012) Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada. European Heart Journal 34: 1002–1011. Available: http://dx.doi.org/10.1093/eurheartj/ehs383.
Publisher:
Oxford University Press (OUP)
Journal:
European Heart Journal
Issue Date:
15-Nov-2012
DOI:
10.1093/eurheartj/ehs383
PubMed ID:
23161701
Type:
Article
ISSN:
0195-668X; 1522-9645
Sponsors:
This work was supported by a Genome Canada Competition III award [Atlantic Medical Genetics and Genomics Initiative (AMGGI)]; the Canadian Foundation for Innovation [New Opportunities Award (9384); Leaders Opportunity Award (13120)]; and Memorial University. Part of this work conducted in the UK was undertaken at UCLH/UCL, which received support from the Department of Health's National Institute of Health Research Biomedical Research Centres funding scheme. Dr. T.-L.Y. is supported by a Canadian Institutes of Health Research-Regional Partnerships Award salary award.
Appears in Collections:
Articles; Computational Bioscience Research Center (CBRC); Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorHaywood, Annikaen
dc.contributor.authorMerner, Nancy D.en
dc.contributor.authorHodgkinson, Kathy A.en
dc.contributor.authorHouston, Jimen
dc.contributor.authorSyrris, Petrosen
dc.contributor.authorBooth, Valerieen
dc.contributor.authorConnors, Seanen
dc.contributor.authorPantazis, Antoniosen
dc.contributor.authorQuarta, Giovannien
dc.contributor.authorElliott, Perryen
dc.contributor.authorMcKenna, Williamen
dc.contributor.authorYoung, Terry Lynnen
dc.date.accessioned2016-01-19T13:21:21Zen
dc.date.available2016-01-19T13:21:21Zen
dc.date.issued2012-11-15en
dc.identifier.citationHaywood AFM, Merner ND, Hodgkinson KA, Houston J, Syrris P, et al. (2012) Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada. European Heart Journal 34: 1002–1011. Available: http://dx.doi.org/10.1093/eurheartj/ehs383.en
dc.identifier.issn0195-668Xen
dc.identifier.issn1522-9645en
dc.identifier.pmid23161701en
dc.identifier.doi10.1093/eurheartj/ehs383en
dc.identifier.urihttp://hdl.handle.net/10754/594089en
dc.description.abstractAimsAutosomal 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 resultsBidirectional 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.ConclusionAlthough 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. © 2012 The Author.en
dc.description.sponsorshipThis work was supported by a Genome Canada Competition III award [Atlantic Medical Genetics and Genomics Initiative (AMGGI)]; the Canadian Foundation for Innovation [New Opportunities Award (9384); Leaders Opportunity Award (13120)]; and Memorial University. Part of this work conducted in the UK was undertaken at UCLH/UCL, which received support from the Department of Health's National Institute of Health Research Biomedical Research Centres funding scheme. Dr. T.-L.Y. is supported by a Canadian Institutes of Health Research-Regional Partnerships Award salary award.en
dc.publisherOxford University Press (OUP)en
dc.subjectArrhythmogenic cardiomyopathiesen
dc.subjectARVC/Den
dc.subjectHaplotypesen
dc.subjectPathogenic variantsen
dc.subjectSegregation analysisen
dc.subjectSudden cardiac deathen
dc.titleRecurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canadaen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.identifier.journalEuropean Heart Journalen
dc.contributor.institutionFaculty of Medicine, Memorial University, St John's, NL, A1B 3V6, Canadaen
dc.contributor.institutionInstitute of Cardiovascular Science, University College London and the Heart Hospital, London W1G 8PH, United Kingdomen
dc.contributor.institutionFaculty of Science, Memorial University, St John's, NL, A1B 3V6, Canadaen
dc.contributor.institutionDiscipline of Genetics, Faculty of Medicine, Memorial University, St. John's, NL AIB 3V6, Canadaen
kaust.authorHaywood, Annikaen

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