Characterization of a novel SCN5A mutation associated with long QT syndrome and arrhythmogenic right ventricular cardiomyopathy in a family.

ABSTRACT

Sudden cardiac death represents a significant diagnostic challenge for forensic pathologists, particularly in inherited arrhythmia syndromes or cardiomyopathies resulting from genetic defects. Molecular autopsies can reveal the underlying molecular etiology in such cases. In this study, we investigated a family with a history of sudden cardiac death to elucidate the molecular basis responsible for sudden cardiac death. The proband underwent a comprehensive forensic examination. Family members received thorough clinical evaluations, including electrocardiogram, Holter monitoring, echocardiography, and cardiac magnetic imaging. Whole exome sequencing and genetic analysis were performed on the deceased and her parents. In addition, Western blotting and patch-clamp recordings were employed to evaluate the expression and function of the mutant protein in vitro. Forensic examination diagnosed arrhythmogenic right ventricular cardiomyopathy (ARVC) as the cause of sudden death. Genetic analysis identified a novel missense mutation in SCN5A (p.V1323L), which was assessed as likely pathogenic by the ACMG guideline. Another family member carrying the mutation manifested long QT syndrome and mild cardiac fibrosis. The cellular electrophysiological study demonstrated that the mutation resulted in an enhanced late sodium current, suggesting it was a gain-of-function mutation. This study characterizes a novel SCN5A mutation that putatively causes long QT syndrome and may contribute to the development of ARVC. Our work expands the pathogenic spectrum of SCN5A variants and underscores the importance of molecular autopsy in sudden death cases, especially in those with suspected genetic disorders.