Novel idiopathic DCM-related <i>SCN5A</i> variants localised in DI-S4 predispose electrical disorders by reducing peak sodium current density.

Abstract

Variants of <i>SCN5A</i>, encoding cardiac sodium channel, have been linked to the development of dilated cardiomyopathy (DCM). We aimed to explore novel <i>SCN5A</i> variants in patients with idiopathic DCM (iDCM) and to identify the distribute characteristics and pathological mechanisms as well as clinical phenotypes associated with the variants in patients with iDCM. <i>SCN5A</i> exons sequencing was performed inpatients with iDCM (n=90) and two control cohorts (arrhythmias group, n=90, and healthy group, n=195). Clinical characteristics were compared between carriers and non-carriers. We then generated a novel heterozygous knock-in (KI) mouse by homologous recombination. Cardiac function, electrical parameters and histological characteristics were examined at basal or stimulating condition. We found three novel non-synonymous <i>SCN5A</i> variants associated with iDCM, including c.674G>A, c.677C>T, and c.4340T>A. The newly defined iDCM-related variants mainly located in the S4 segment of domain I (DI-S4). Incidence of atrioventricular block was significantly higher in mutant patients with iDCM than in non-carriers. Structural injuries were absent at both basal and stress condition in KI mice carrying c.674G>A (R225Q); however, this variant significantly prolonged PR intervals at baseline without affecting other ECG parameters, which was linked to decreased peak sodium current density in KI cardiomyocytes. Histological analysis of the atrioventricular node did not show any evidences of cell damages. Our results suggest that the iDCM-related <i>SCN5A</i> variants in the DI-S4 could predispose electrical disorders by reducing peak sodium current density.