Description:
<jats:title>Abstract</jats:title><jats:p>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 Ca<jats:sup>2+</jats:sup> handling in WT and mutant human <jats:italic>RYR2</jats:italic> transfected HEK293 cells by fluorescent microscopy and an enhanced store overload-induced Ca<jats:sup>2+</jats:sup> release in response to cytosolic Ca<jats:sup>2+</jats:sup> 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 Ca<jats:sup>2+</jats:sup> handling and cardiac conduction suggests a possible oligogenic origin for the ectopies originating from Purkinje fibres.</jats:p>