TY - JOUR
T1 - Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada
AU - Haywood, Annika
AU - Merner, Nancy D.
AU - Hodgkinson, Kathy A.
AU - Houston, Jim
AU - Syrris, Petros
AU - Booth, Valerie
AU - Connors, Sean
AU - Pantazis, Antonios
AU - Quarta, Giovanni
AU - Elliott, Perry
AU - McKenna, William
AU - Young, Terry Lynn
N1 - KAUST Repository Item: Exported on 2020-10-01
Acknowledgements: 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.
PY - 2012/11/15
Y1 - 2012/11/15
N2 - 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.
AB - 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.
UR - http://hdl.handle.net/10754/594089
UR - https://academic.oup.com/eurheartj/article-lookup/doi/10.1093/eurheartj/ehs383
UR - http://www.scopus.com/inward/record.url?scp=84875967348&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehs383
DO - 10.1093/eurheartj/ehs383
M3 - Article
C2 - 23161701
SN - 0195-668X
VL - 34
SP - 1002
EP - 1011
JO - European Heart Journal
JF - European Heart Journal
IS - 13
ER -