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Calcium (Ca 2+ ) 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 Ca 2+ can cause different types of cardiac dysfunction. Thus, the remodeling of Ca 2+ 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, Ca 2+ levels are regulated by several Ca 2+ -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.

Mitral valve prolapse (MVP) is a common valvular heart defect with variable outcomes. Several studies reported MVP as an underestimated cause of life-threatening arrhythmias and sudden cardiac death (SCD), mostly in young adult women. Herein, we report a clinical and genetic investigation of a family with bileaflet MVP and a history of syncopes and resuscitated sudden cardiac death. Using family based whole exome sequencing, we identified two missense variants in the SCN5A gene. A rare variant SCN5A :p.Ala572Asp and the well-known functional SCN5A :p.His558Arg polymorphism. Both variants are shared between the mother and her daughter with a history of resuscitated SCD and syncopes, respectively. The second daughter with prodromal MVP as well as her healthy father and sister carried only the SCN5A :p.His558Arg polymorphism. Our study is highly suggestive of the contribution of SCN5A mutations as the potential genetic cause of the electric instability leading to ventricular arrhythmias in familial MVP cases with syncope and/or SCD history.

Left Ventricular Non-Compaction (LVNC) is defined by the triad prominent myocardial trabecular meshwork, thin compacted layer, and deep intertrabecular recesses. LVNC associated with dilation is characterized by the coexistence of left ventricular dilation and systolic dysfunction. Pediatric cases with dilated-LVNC have worse outcomes than those with isolated dilated cardiomyopathy and adult patients. Herein, we report a clinical and genetic investigation using trio-based whole-exome sequencing of a pediatric case with early-onset dilated-LVNC. Compound heterozygous mutations were identified in the Striated Muscle Enriched Protein Kinase ( SPEG ) gene, a key regulator of cardiac calcium homeostasis. A paternally inherited mutation: SPEG ; p.(Arg2470Ser) and the second variant, SPEG ; p.(Pro2687Thr), is common and occurred de novo. Subsequently, Sanger sequencing was performed for the family in order to segregate the variants. Thus, the index case, his father, and both sisters carried the SPEG : p.(Arg2470Ser) variant. Only the index patient carried both SPEG variants. Both sisters, as well as the patient's father, showed LVNC without cardiac dysfunction. The unaffected mother did not harbor any of the variants. The in silico analysis of the identified variants (rare and common) showed a decrease in protein stability with alterations of the physical properties as well as high conservation scores for the mutated residues. Interestingly, using the Project HOPE tool, the SPEG ; p.(Pro2687Thr) variant is predicted to disturb the second fibronectin type III domain of the protein and may abolish its function. To our knowledge, the present case is the first description of compound heterozygous SPEG mutations involving a de novo variant and causing dilated-LVNC without neuropathy or centronuclear myopathy.