Abstract
BACKGROUND: SCN5A is the most common susceptibility gene in patients with Brugada syndrome (BrS); however, the interpretation and management of benign or variants of unknown clinical significance (VUS) in SCN5A remains a challenge despite the availability of genetic testing. OBJECTIVE: This study aimed to investigate the relationship between the SCN5A variants and clinical symptoms of BrS patients. METHODS: We resequenced the SCN5A gene in 239 patients diagnosed with BrS at Hiroshima University Hospital and analyzed the association between the SCN5A variants and clinical features, 12-lead electrocardiography (ECG) parameters, and signal-averaged ECG. RESULTS: Overall, 84 SCN5A variants were identified: 55 benign, 7 pathogenic, and 22 VUS. No significant difference in the incidence of previous cardiac events was observed between patients with and without SCA5A benign variants. The female proportion was higher in BrS patients with SCN5A VUS or pathogenic variants. Moreover, the symptomatic proportion was higher in BrS patients with SCN5A VUS or pathogenic variants than in those without SCN5A variants. Multivariate analyses revealed that the presence of SCN5A pathogenic variants, longer r-J intervals in lead V1, and the presence of fragmented QRS were independently associated with cardiac events in BrS patients, and that positive late potentials, longer LAS40, and lower RMS40 were significantly associated with symptomatic BrS in patients carrying SCN5A VUS. CONCLUSIONS: SCN5A pathogenic variants were found to be independent risk factors for cardiac events in BrS patients. Although SCN5A VUS was not an independent risk factor for cardiac events, proportion of symptomatic patients was higher in BrS patients with SCN5A VUS than in those without SCN5A variants. In BrS patients with SCN5A VUS, the signal-averaged ECG was the key to the risk stratification for cardiac events.