title: Recurrent missense mutations in TMEM43 (ARVD5) due to founder effects cause arrhythmogenic cardiomyopathies in the UK and Canada.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Faculty of Medicine, Memorial University, St John's, Newfoundland and Labrador, Canada A1B 3V6.
authors.forename: Annika F M
authors.initials: AF
authors.lastname: Haywood
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Merner
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Hodgkinson
authors.forename: Jim
authors.initials: J
authors.lastname: Houston
authors.forename: Petros
authors.initials: P
authors.lastname: Syrris
authors.forename: Valerie
authors.initials: V
authors.lastname: Booth
authors.forename: Sean
authors.initials: S
authors.lastname: Connors
authors.forename: Antonios
authors.initials: A
authors.lastname: Pantazis
authors.forename: Giovanni
authors.initials: G
authors.lastname: Quarta
authors.forename: Perry
authors.initials: P
authors.lastname: Elliott
authors.forename: William
authors.initials: W
authors.lastname: McKenna
authors.forename: Terry-Lynn
authors.initials: TL
authors.lastname: Young
mesh_terms: D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D016022:Case-Control Studies; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D005260:Female; D018703:Founder Effect; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D009523:Newfoundland and Labrador / Q000453:epidemiology; D012008:Recurrence; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D008565:Membrane Proteins; C528696:TMEM43 protein, human