Clinical spectrum and phenotypic characteristics of patients with SCN5A variants and cardiomyopathy: early insights from an International Cohort

Background Genetic variants in the SCN5A gene, which codes for the cardiac sodium channel, are primarily linked with electrical heart diseases such as Brugada syndrome, and these have been well characterized. However, SCN5A variants have also been implicated in cardiomyopathies. The clinical presentation of patients harbouring an SCN5A variant and presenting with structural heart disease remains poorly understood. Here, we present preliminary findings from our multicenter, international cohort. Results In this retrospective, international, multicenter cohort we analyzed 34 patients (54% male; median age at onset 40 years) with heterozygous, P/LP/VUS SCN5A variants, presenting with cardiomyopathy. At baseline, 32% (n=11) met criteria for dilated cardiomyopathy (DCM), 9% (n=3) for arrhythmogenic cardiomyopathy (ACM, Padua 2020), 26% (n=9) for ARVC (2010), 12% (n=4) for hypertrophic cardiomyopathy (HCM), 15% (n=5) had unclassified SCN5A-related cardiomyopathy, 3% (n=1) showed a DCM/ACM overlap and 3% (n=1) had a NDLVC phenotype. Among 24 patients with variants mapped to specific functional domains, 6 localized to transmembrane linkers, 5 to N- or C-termini, and 5 to pore-forming regions. The most frequent ECG abnormality was intraventricular conduction delay (40%), with T-wave inversions mainly in anterior (V1–V3, 31%) and lateral leads (V4–V6, 29%). Conduction disturbances included right bundle branch block in 17% and left bundle branch block in 3%; atrial fibrillation occurred in 3%. Median LVEF was 55% (IQR 37–59%), median FAC 45% (IQR 36–50%), and median LVEDD 52 mm (IQR 46.5–55). Dilated LV was present in 29%, and regional wall motion abnormalities were observed in 6 (RV) and 10 (LV) patients. Conclusions Patients with an SCN5A variant being associated with structural heart disease in our cohort most commonly exhibited a DCM phenotype, ARVC, as well as otherwise unclassified SCN5A-related cardiomyopathy. Despite preserved median LVEF and FAC (55% and 45% respectively) at baseline, regional wall motion abnormalities were already detectable in a substantial fraction of patients, implying that early structural changes may precede overall functional decline in SCN5A-related cardiomyopathies. In contrast to classical channelopathies, where a clustering of SCN5A variants along "canonical" voltage-sensor hotspots is frequently seen, in our cohort there was a variant shift towards cytoplasmic termini and inter-segment linkers; More research is needed to substantiate or refute the hypothesis that structural and electrical SCN5A phenotypes may arise from different variant topologies.