A Comprehensive Analysis of Non-Desmosomal Rare Genetic Variants in Arrhythmogenic Cardiomyopathy: Integrating in Padua Cohort Literature-Derived Data

Int J Mol Sci. 2024 Jun 6;25(11):6267. doi: 10.3390/ijms25116267.

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disease at risk of sudden death. Genetic testing impacts greatly in ACM diagnosis, but gene-disease associations have yet to be determined for the increasing number of genes included in clinical panels. Genetic variants evaluation was undertaken for the most relevant non-desmosomal disease genes. We retrospectively studied 320 unrelated Italian ACM patients, including 243 cases with predominant right-ventricular (ARVC) and 77 cases with predominant left-ventricular (ALVC) involvement, who did not carry pathogenic/likely pathogenic (P/LP) variants in desmosome-coding genes. The aim was to assess rare genetic variants in transmembrane protein 43 (TMEM43), desmin (DES), phospholamban (PLN), filamin c (FLNC), cadherin 2 (CDH2), and tight junction protein 1 (TJP1), based on current adjudication guidelines and reappraisal on reported literature data. Thirty-five rare genetic variants, including 23 (64%) P/LP, were identified in 39 patients (16/243 ARVC; 23/77 ALVC): 22 FLNC, 9 DES, 2 TMEM43, and 2 CDH2. No P/LP variants were found in PLN and TJP1 genes. Gene-based burden analysis, including P/LP variants reported in literature, showed significant enrichment for TMEM43 (3.79-fold), DES (10.31-fold), PLN (117.8-fold) and FLNC (107-fold). A non-desmosomal rare genetic variant is found in a minority of ARVC patients but in about one third of ALVC patients; as such, clinical decision-making should be driven by genes with robust evidence. More than two thirds of non-desmosomal P/LP variants occur in FLNC.

Keywords: DES; FLNC; TMEM43; arrhythmogenic cardiomyopathy; dilated cardiomyopathy; “non-desmosomal” genes.

MeSH terms

  • Adult
  • Antigens, CD / genetics
  • Arrhythmogenic Right Ventricular Dysplasia* / genetics
  • Cadherins / genetics
  • Calcium-Binding Proteins / genetics
  • Desmosomes / genetics
  • Desmosomes / metabolism
  • Female
  • Filamins / genetics
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Italy
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Retrospective Studies

Substances

  • Membrane Proteins
  • Cadherins
  • Filamins
  • phospholamban
  • TMEM43 protein, human
  • FLNC protein, human
  • CDH2 protein, human
  • Calcium-Binding Proteins
  • Antigens, CD