**1. Introduction**

The alpha subunit of the cardiac voltage-gated sodium channel NaV1.5 (*SCN5A*), which is responsible for the rapid depolarization phase of the cardiac action potential, has been one of the first studied ion channels since the early days of cardiovascular genetic research [1–3]. Unlike other cardiac-relevant genes that are typically implicated in either cardiac channelopathies or cardiomyopathies, rare variants in *SCN5A* have been associated with an incredibly diverse spectrum of frequently overlapping electrical and structural phenotypes. Loss-of-function variants have been linked to Brugada syndrome [4], progressive cardiac conduction disease (PCCD) [5], congenital atrioventricular block [6], sick sinus syndrome [7], idiopathic ventricular fibrillation [3], and atrial standstill [8], while gain-of-function variants have been associated with long QT syndrome type 3 [1], and multifocal ectopic Purkinje-related premature contractions (MEPPC) [9]. Other *SCN5A*-mediated conditions such as familial atrial fibrillation [10], sudden infant death syndrome [11], familial dilated cardiomyopathy (DCM) [8,12], and, rarely, arrhythmogenic right ventricular cardiomyopathy (ARVC) [13], have a more complex pathophysiology with involvement of multiple molecular phenotypes. A great variation of phenotypes has been noted even within the affected families and in individual patients over time, but to date, genotype–phenotype analyses have not been able to explain this variation in a clinical phenotype.

Of more than 450 disease-causing *SCN5A* variants identified, only a handful have been linked to DCM [12]. Pathogenic/likely pathogenic variants in *SCN5A* are associated with a substantially higher burden of atrial and ventricular arrhythmias (in >90% of cases), cardiac conduction disease, and higher risk of sudden cardiac death [12,14–16]. While mechanisms underlying different electrical phenotypes have been profoundly studied using in vitro and in vivo approaches, little is known about how sodium channel malfunction leads to ventricular dysfunction and dilation. A critical appraisal of the existing scientific evidence might add another missing piece to this puzzle.
