期刊
EUROPEAN HEART JOURNAL
卷 34, 期 13, 页码 1002-1011出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehs383
关键词
ARVC/D; Sudden cardiac death; Segregation analysis; Pathogenic variants; Haplotypes; Arrhythmogenic cardiomyopathies
资金
- Genome Canada [Atlantic Medical Genetics and Genomics Initiative (AMGGI)]
- Canadian Foundation for Innovation [9384, 13120]
- Memorial University
- Department of Health's National Institute of Health Research Biomedical Research Centres funding scheme
- Canadian Institutes of Health Research-Regional Partnerships Award salary award
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.
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