Familial Characterization of the DSC2 c.354+1G>T Splice-Site Variant Cardiac Disease
TL;DR
The findings support genetic counseling, cascade testing, and cardiovascular surveillance, however, the current clinical and segregation data do not establish definitive causality for hypertrophic cardiomyopathy or conduction disease.
Abstract
Arrhythmogenic cardiomyopathy is an inherited myocardial disease frequently associated with variants in desmosomal genes. DSC2 encodes desmocollin-2, a cadherin involved in cardiomyocyte adhesion at the intercalated disc; disruption of desmosomal integrity may contribute to myocardial remodeling and arrhythmogenic susceptibility. We describe a Panamanian family in which the DSC2 splice-site variant c.354+1G>T (NM_024422.6) was identified during evaluation for suspected inherited cardiac disease. The proband was a 66- year-old woman with hypertrophic cardiomyopathy, concentric hypertrophy on echocardiography, and high-risk syncope. Her 86-year-old mother had cardiac conduction disease requiring pacemaker implantation, and the proband’s daughter was identified as a carrier. The variant affects the canonical +1 donor splice site and is predicted to alter pre-mRNA splicing, with SpliceAI donor-loss score of 0.96, Pangolin splice-loss score of 0.64, CADD PHRED score of 33, and PhyloP score of 8.87. ClinVar classifies the variant as likely pathogenic. These findings support genetic counseling, cascade testing, and cardiovascular surveillance. However, the current clinical and segregation data do not establish definitive causality for hypertrophic cardiomyopathy or conduction disease.