Desmoglein-2 related Arrhythmogenic Cardiomyopathy: Integrative Genomic and Literature-based analysis with an Italian cohort-Level Validation

Abstract Desmoglein-2 (DSG2) is a crucial desmosomal cadherin expressed in cardiomyocytes that contributes significantly to the development of arrhythmogenic cardiomyopathy (ACM), a condition characterized by variable onset and clinical presentation. In this study, we conducted an integrative analysis that merges a systematic review of the literature, data from large-scale population databases, and findings from a well-phenotyped Italian ACM validation cohort (n = 95). While pathogenic variants, “hot-VUS,” and copy number alterations were primarily located in calcium-binding extracellular domains, the furin cleavage site, and cytoplasmic anchoring motifs, these alone were insufficient to explain disease manifestation, with penetrance estimated at just 42%. In contrast, biallelic and digenic variants correlated with earlier onset, more severe biventricular involvement, and complete penetrance. Structural modeling and protein stability analyses confirmed disruption of key functional domains. These results underscore the complexity of DSG2-related ACM and advocate for domain- and multilocus-informed diagnostic strategies, along with comprehensive genetic screening and sustained clinical follow-up for effective risk stratification in affected families.