SCN5A Cardiomyopathy: from Ion Channel Dysfunction To Clinical Disease

Although SCN5A variants are an established cause of arrhythmia and conduction disease, their association with dilated cardiomyopathy (DCM) is less studied. This review summarizes recent insights into SCN5A-related cardiomyopathy, focusing on genotype-phenotype correlations, overlap with arrhythmia, and implications for management.

Both gain- and loss-of-function SCN5A variants are associated with cardiomyopathy, found in 0.5-0.9% of DCM cases. Presentation ranges from isolated DCM to overlap phenotypes, in both pediatric and adult patients. High variability and intrafamilial heterogeneity suggest pleiotropic effects and variable penetrance. High prevalence of arrhythmias and conduction disease suggests the DCM phenotype may be mediated by electrical disturbances. However, functional studies and cases without prior arrhythmia suggest SCN5A variants may directly contribute to structural myocardial changes. SCN5A-related cardiomyopathy is a rare disorder at the intersection of structural and electrical heart disease. Genotype-informed strategies, including arrhythmia management, and early cascade genetic screening are clinically relevant. Further research should address SCN5A-specific risk management in DCM patients.