Stéphane Zaffran

Calcium (Ca2+) is the major mediator of cardiac contractile function. It plays a key role in regulating excitation–contraction coupling and modulating the systolic and diastolic phases. Defective handling of intracellular Ca2+ can cause different types of cardiac dysfunction. Thus, the remodeling of Ca2+ handling has been proposed to be a part of the pathological mechanism leading to electrical and structural heart diseases. Indeed, to ensure appropriate electrical cardiac conduction and contraction, Ca2+ levels are regulated by several Ca2+-related proteins. This review focuses on the genetic etiology of cardiac diseases related to calcium mishandling. We will approach the subject by focalizing on two clinical entities: catecholaminergic polymorphic ventricular tachycardia (CPVT) as a cardiac channelopathy and hypertrophic cardiomyopathy (HCM) as a primary cardiomyopathy. Further, this review will illustrate the fact that despite the genetic and allelic heterogeneity of cardiac defects, calcium-handling perturbations are the common pathophysiological mechanism. The newly identified calcium-related genes and the genetic overlap between the associated heart diseases are also discussed in this review.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic syndrome characterized by life‐threatening arrhythmias, a normal resting electrocardiogram and the absence of overt structural heart abnormalities. Mutations in RyR2 gene account for the large part of CPVT cases. Less frequently, mutations in CASQ2 gene have been linked to the recessive form of the disease. Overall, approximately 35% of CPVT patients remain without a genetic etiology implying that other genes might be found causative of the disease. Here, we present a 6‐year‐old boy born to first‐degree related parents, with a typical phenotype of CPVT and a family history of sudden cardiac death of his brother at 7 years. A trio‐based whole exome sequencing was performed, and we identified a homozygous variant in AGRN gene and a heterozygous variant in RPL3L gene. We hypothesized that the presence of the homozygous variant in AGRN accounts for the CPVT phenotype in this family and the heterozygous variant in RPL3L gene may act as a modifier gene. Further studies are needed to determine the role of these genes in CPVT.