Abstract
Idiopathic ventricular fibrillation (IVF) causes sudden death in young adult patients without structural or ischemic heart disease. Most IVF cases are sporadic and some patients present with short-coupled torsade de pointes, the genetics of which are poorly understood. A man who had a first syncope at the age of 35 presented with frequent short-coupled premature ventricular beats with bursts of polymorphic ventricular tachycardia and then died suddenly. By exome sequencing, we identified three rare variants: p.I784F in the SPRY1 of the ryanodine receptor 2 (RyR2), p.A96S in connexin 40 (Cx40), reported to affect electrical coupling and cardiac conduction, and a nonsense p.R244X in the cardiac-specific troponin I-interacting kinase (TNNI3K). We assessed intracellular Ca2+ handling in WT and mutant human RYR2 transfected HEK293 cells by fluorescent microscopy and an enhanced store overload-induced Ca2+ release in response to cytosolic Ca2+ was observed in RyR2-I784F cells. In addition, crystal structures and thermal melting temperatures revealed a conformational change in the I784F-SPRY1 domain compared to the WT-domain. The novel RyR2-I784F variant in SPRY1 domain causes a leaky channel under non-stress conditions. The presence of several variants affecting Ca2+ handling and cardiac conduction suggests a possible oligogenic origin for the ectopies originating from Purkinje fibres.
Highlights
Idiopathic ventricular fibrillation (IVF) causes sudden death in young adult patients without structural or ischemic heart disease
Using a two-way Analysis of Variance (ANOVA) test, we found that C a2+ oscillation frequencies differed as a function of expressed variant (RyR2-I784F vs ryanodine receptor 2 (RyR2)-WT; p < 0.0001), C a2+ concentrations (p < 0.0001) and cAMP stimulation (p < 0.0001) with strong relationship between Ca2+ concentration and cAMP treatment (Fig. 3b,c)
Following exome sequencing we identified three variants of interest: (1) a novel RYR2 variant that results in the substitution of isoleucine for phenylalanine at position 784 (RyR2-I784F), located in the SPRY1 domain, outside of the catecholaminergic polymorphic ventricular tachycardia (CPVT)-associated RyR2 mutational hotspot regions and affecting an evolutionary conserved residue; (2) a missense variant in GJA5 leading to the substitution of alanine at position 96 for a serine (GJA5-A96S), previously reported as pathogenic[29]; and (3) a nonsense variant in TNNI3K which results in a stop codon at position 244 (TNNI3K-R244X)
Summary
Idiopathic ventricular fibrillation (IVF) causes sudden death in young adult patients without structural or ischemic heart disease. Current guidelines define IVF as a diagnosis of exclusion in patients who have survived a VF episode without any identifiable structural or metabolic cause, as assessed by clinical evaluation of known cardiac, respiratory, metabolic and toxicological etiologies that may lead to cardiac arrest[2]. Genetic screening of known genes responsible for arrhythmias led to the identification of only a few variants in a small percentage of c ases[6] This suggests that these patients are genetically heterogeneous and that the IVF is likely oligogenic in origin, which could explain the low penetrance in the families. Several variants have been identified recently in the ryanodine receptor 2 (RyR2) gene in scTdP p atients[12,13,14]
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