Cason M, Celeghin R, Marinas MB, et al. - Researchers sought to determine molecular pathways underlying early arrhythmogenic cardiomyopathy (AC) via gene expression profiling in both humans as well as animal models. They conducted RNA sequencing for differentially expressed genes (DEGs) on the myocardium of transgenic mice overexpressing the Desmoglein2-N271S mutation prior to phenotype onset. Among 10 genotype-negative AC patients, whole exome sequencing was conducted, and experts performed subsequent direct sequencing using 140 AC index cases. Of 29 DEGs detected at early disease stages, Lgals3/GAL3 (lectin, galactoside-binding, soluble, 3) demonstrated decreased cardiac expression in transgenic mice as well as in 3 AC patients who experienced sudden cardiac death without overt structural remodeling. In 5 human AC probands, experts found four rare missense variants of LGALS3. Overall, findings demonstrated a crucial role of GAL3 in early AC onset, via regulation of Wnt/β-catenin signaling as well as intercellular adhesion.