SCN5A c.4720G> A: a rare genetic variant associated with familial sick sinus syndrome and sudden cardiac death.

BACKGROUND: The cardiac voltage-gated sodium channel Nav1.5, encoded by SCN5A, plays a critical role in cardiac electrophysiology. SCN5A variants represent a series of frequently identified genetic findings in molecular autopsies, with established associations across multiple arrhythmia syndromes including long QT syndrome type 3, Brugada syndrome, progressive cardiac conduction disease, sinus node dysfunction, atrial fibrillation, atrial standstill, and dilated cardiomyopathy. Recently, an increasing number of familial cases with early-onset sick sinus syndrome (SSS) were reported, bringing more challenges in forensic genetic diagnosis. METHODS: We investigated a four-generation family with SSS, characterized by a history of pacemaker implantation and sudden cardiac death (SCD). Genetic analyses were performed to identify the underlying pathogenic variant, and electrophysiological properties were evaluated using patch-clamp recordings. RESULTS: We identified a rare SCN5A missense variant, NM_198056.3(SCN5A,rs199473620): c.4720G>A (p.E1574K), in this family. Subsequent analyses demonstrated that the mutated site is highly conserved in the voltage-gated sodium channel family, as well as across species. Electrophysiological experiments showed that this mutation significantly attenuated the function of Nav1.5 channel, potentially revealing the pathogenic mechanism of SCN5A c.4720G>A variant. CONCLUSIONS: Our study identified a rare SCN5A missense variant and classified it as likely pathogenic following the ACMG framework, thereby expanding the phenotypic spectrum of SCN5A-associated SSS and providing a potential forensic diagnostic molecular target for unexplained deaths with negative morphological alterations.