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

• Published in: European Heart Journal
• Main 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
• Other Authors: Biological and Environmental Sciences and Engineering (BESE) Division, Computational Bioscience Research Center (CBRC), Faculty of Medicine, Memorial University, St John's, NL, A1B 3V6, Canada, Institute of Cardiovascular Science, University College London and the Heart Hospital, London W1G 8PH, United Kingdom, Faculty of Science, Memorial University, St John's, NL, A1B 3V6, Canada, Discipline of Genetics, Faculty of Medicine, Memorial University, St. John's, NL AIB 3V6, Canada
• Format: Article in Journal/Newspaper
• Language: unknown
• Published: Oxford University Press (OUP) 2012
• Subjects: Arrhythmogenic cardiomyopathies; ARVC/D; Haplotypes; Pathogenic variants; Segregation analysis; Sudden cardiac death; Newfoundland
• Online Access: http://hdl.handle.net/10754/594089; https://doi.org/10.1093/eurheartj/ehs383

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. 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 ...