In silico validation revealed the role of SCN5A mutations and their genotype-phenotype correlations in Brugada syndrome

Background: Brugada syndrome (BrS) is a rare genetic disease that causes sudden cardiac death (SCD) and arrhythmia. SCN5A pathogenic variants (about 30% of diagnosed patients) are responsible for BrS.

Aims: Lack of knowledge regarding molecular characteristics and the correlation between genotype and phenotype interfere with the risk stratification and finding the optimal treatment in Vietnam. Therefore, we identified SCN5A variants and evaluated the genotype-phenotype correlation of BrS on 117 Vietnamese probands.

Materials and methods: The clinical characteristics and blood samples of BrS patients were collected. To determine SCN5A variants, Sanger sequencing was conducted, and subsequently, these variants were analyzed by bioinformatic tools.

Results: In this cohort, the overall rate of detected variants in SCN5A was 25.6%, which could include both pathogenic and benign variants. In genetic testing, 21 SCN5A variants were identified, including eight novels and 15 published variants. Multiple bioinformatic tools were used to predict variant effect with c.551A>G, c.1890+14G>A, c.3338C>T, c.3578G>A, and c.5484C>T as benign, while other variants were predicted as disease-causing. The family history of SCD (risk ratio [RR] = 4.324, 95% CI: 2.290-8.269, p < 0.001), syncope (RR = 3.147, 95% CI: 1.668-5.982, p = 0.0004), and ventricular tachycardia/ventricular fibrillation (RR = 3.406, 95% CI: 1.722-5.400, p = 0.0035) presented a significantly higher risk in the SCN5A (+) group, consisting of individuals carrying any variant in the SCN5A gene, compared to SCN5A (-) individuals.

Conclusion: The results contribute to clarifying the impact of SCN5A variants on these phenotypes. Further follow-up studies need to be carried out to understand the functional effects of these SCN5A variants on the severity of BrS.