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Aims  Likely 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.    Methods  We 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.    Results  Forty 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.    Conclusions  Although  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.

No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy