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Loss-of-function variants in the sodium channel α-subunit (SCN5A) are associated with Brugada Syndrome (BrS). As Southeast Asians are understudied, the detected variants often lack supporting evidence and are absent in current clinical databases. This creates a challenge as variant interpretation resulted in over 90% of rare variants detected being classified as variants of uncertain significance (VUS) according to ACMG guideline.
To investigate the burden of rare SCN5A variants in Thai BrS patients and to examine the clinical characteristics of BrSpatients with rare SCN5A variants.
Burden testing was performed on 196 cases and 394 controls. Rare variants, with allele frequency in gnomAD database (AF < 0.001), were included. Testing was further performed on variants prioritized with CADD score, a measure of variant deleteriousness (CADD>25). Clinical characteristics of Brugada Syndrome patients with rare SCN5A variants were assessed.
Rare SCN5A variants are associated with Thai BrS cases (p= 0.04, 8.16% vs 3.04%). An enrichment of prioritized variants was observed in BrS cases (p= 2.31x10-(5), 5.61% vs 0.5% ). No significant differences were found in clinical characteristics of patients with and without rare SCN5A variants. However, patients with prioritized SCN5A variants (n=11) showed significantly earlier age-onset of first cardiac event when compared to patients with rare SCN5A variants (p < 0.02, upper figure) and other BrS cases in the cohort (p < 0.01 lower figure).