Comprehensive genetic analysis of desmoglein-2 in arrhythmogenic cardiomyopathy

Abstract Background Desmoglein-2 (DSG2, MIM#610193) is a transmembrane desmosomal glycoprotein in which primarily truncating variants cause arrhythmogenic cardiomyopathy (ACM) (OMIM#107970; ORPHA247), characterized by electrical instability and myocardial fibro-fatty replacement. An undefined number of DSG2 missense variants have been reported, but their role in ACM pathogenesis and the clinical impact remains an open question. Aim This study aims to evaluate the current understanding of DSG2 gene variants through a multiphase approach, with the goal of refining variant interpretation and enhancing their clinical applicability for clinical decision-making. Methods Pubmed records satisfying inclusion criteria for the analysis of DSG2-related variants along with Genome Aggregation Database (GnomAD) or ClinVar databases were investigated. Genetic variants were reclassified according to the current American College of Medical Genetics and Genomics (ACMG) recommendations, as Likely Pathogenic (LP), Pathogenic (P), and Variants of Uncertain Significance (VUS, 1-4 points). An independent validation cohort of ACM underwent whole exome Sequencing (WES) and bioinformatic tools (IonCom, DynaMut, AlphaFold) were used to predict the pathogenicity of specific variants and their effect on DSG2 protein. Results A total of 107 records met the inclusion criteria, identifying 90 missense and truncating variants described in literature. As of now, the GnomAD database lists 3,570 DSG2 variants, with coding variants primarily found in the extracellular (ECs 1-4, 28%) and cytoplasmic domains (21%, mainly RUD). Nearly half of these are missense variants but, only 1% are classified as LP/P. In contrast, truncating variants are more frequently classified as LP/P. The ClinVar database reports 1,847 DSG2 variants associated with ACM, predominantly classified as VUS and linked to cardiac phenotypes. In our validation cohort of 94 ACM patients (45 probands), 22 heterozygous DSG2 variants were identified as hotVUS or LP/P, with scores ranging from 5 to 17 points. Following cascade genetic screening in families and in vitro assays, only eight missense variants met the ACMG criteria for classification as LP or hotVUS. Conclusions DSG2 variants are associated with a broad ACM spectrum, ranging from mild to severe manifestations of the disease. A review of the literature and database analysis revealed that most DSG2 variants are missense, requiring further functional studies and clinical data to better determine their significance and improve variant interpretation.