SCN5A missense variants and their contribution to deaths in Sudden Unexplained Nocturnal Death Syndrome (SUNDS)

Sudden Unexplained Nocturnal Death Syndrome (SUNDS), locally known as Lai-tai in Thailand, leads to sudden death during sleep in otherwise healthy young males. Cardiac arrhythmias, including Brugada syndrome (BrS) and Long QT syndrome (LQTS), are often implicated, with mutations in the SCN5A gene, encoding the Na_v1.5 sodium channel, strongly linked to both conditions. This study characterized postmortem SUNDS cases in Thailand and analyzed SCN5A gene variants using whole exome sequencing (WES) and molecular modeling. Forensic autopsies were performed on 98 SUNDS victims from August 2020 to February 2023. WES was applied to 98 SUNDS-related genes, filtering variants based on dbNSFP annotations and public databases like the 1000 Genomes Project. Three SCN5A variants (A665S, R179Q, and R965C) were detected in five cases (approximate for 5 %). One case of A665S, which was reported for the first time in Thailand, was discovered. The R179Q variant was identified in an additional case, but it did not have a substantial electrostatic surface impact on Na_v1.5. In contrast, the R965C variant, which is frequently associated with BrS, was discovered in three cases (approximate for 3 %). These results imply that SCN5A variants are involved in the pathogenesis of SUNDS and may provide valuable genetic markers for the purpose of diagnosis and prevention.