Pleiotropic effects of SCN5A variants: linking electrical dysfunction to structural cardiomyopathy, insights from a single-center case series

Background The SCN5A gene encodes the α-subunit of the cardiac sodium channel Nav1.5, which is responsible for the rapid depolarization phase of the cardiomyocyte action potential. Pathogenic variants can alter channel function, leading to cardiac channelopathies. Although historically associated with Brugada syndrome, SCN5A is now recognized as a pleiotropic gene implicated in long QT syndrome type 3, conduction disorders, dilated cardiomyopathy, and other arrhythmic conditions. Purpose The aim of this study was to describe the heterogeneous phenotypes associated with SCN5A variants identified in our center and to highlight their different clinical and structural manifestations, assessed through detailed electrophysiological evaluation and advanced cardiac imaging. Methods We conducted a monocentric retrospective observational study. A total of 287 patients referred for genetic testing for suspected arrhythmic disorders were analyzed: 74 (26%) with suspected Brugada syndrome, 15 (5%) with family history of Brugada syndrome, 126 (44%) with suspected dilated cardiomyopathy, and 72 (25%) with suspected arrhythmogenic cardiomyopathy. 40 patients (13.9%) carried a pathogenic/likely pathogenic variant or variant of uncertain significance (VUS) in SCN5A. Seven (17.5%) of them presented atypical phenotypes compared to classical Brugada manifestations. After flecainide/ajmaline challenge, none of the patients developed a type 1 Brugada pattern. Results 3 patients (42.8%) exhibited features consistent with arrhythmogenic cardiomyopathy, 2 (28.6%) with dilated cardiomyopathy, 1 (14.3%) with short QT syndrome, and 1 (14.3%) with ventricular fibrillation and out-of-hospital cardiac arrest, with only non-ischemic inferolateral intramyocardial late gadolinium enhancement (LGE) at cardiac MRI. Structural abnormalities were detected in 3 cases (42.8%), including left ventricular adipose metaplasia and inferolateral LGE associated with low-voltage areas on endocardial mapping. No patient showed a type 1 Brugada pattern after drug challenge. Conclusions Genotype–phenotype correlation confirms that SCN5A is not merely a channelopathy gene but also a potential cardiomyopathy gene, linking electrical dysfunction with structural remodeling. Sodium current alterations may lead to electrical instability, conduction delay, fibrosis, and ventricular dilation, resulting in overlapping phenotypes. Our findings are consistent with recent evidence supporting the pleiotropic role of SCN5A, involved in approximately 1–2% of arrhythmogenic cardiomyopathy cases and several dilated cardiomyopathies. These results highlight the need to include SCN5A variants not only in the diagnostic work-up of channelopathies but also in the genetic evaluation of dilated and arrhythmogenic cardiomyopathies with complex electrical phenotypes.