Abstract
AimsLikely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure.MethodsWe screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant.ResultsForty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants.ConclusionsAlthough PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development.
Highlights
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable progressive heart condition characterized by fibro-fatty replacement of the ventricular myocardium [1]
Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively)
PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and does not support a major role for PLEC in this disorder
Summary
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable progressive heart condition characterized by fibro-fatty replacement of the ventricular myocardium [1]. ARVC is most commonly transmitted as an autosomal dominant trait [2] and has an estimated prevalence of ~1:2500 [3]. ARVC patients suffer from ventricular arrhythmias, syncope, and sudden cardiac death as early as young adulthood [5], with the majority of cases diagnosed before the age of 40 years [6]. Identification of ARVC-associated variants greatly facilitates the identification of family members at risk and provides a better understanding of the underlying pathophysiological mechanisms [1]. While more ARVC-associated genes are known [7], they only contribute to a small proportion of cases of this predominantly desmosomal disease, and roughly half of ARVC cases remain gene elusive [8]
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