Ryanodine receptor 2 (RYR2) is one of the major components of a calcium channel that supplies calcium to cardiac muscle cells and mediates sarcoplasmic release of stored calcium ions, thereby playing a key role in triggering cardiac muscle contraction. Defects in the RYR2 gene may cause autosomal dominant ventricular arrhythmias, including catecholaminergic polymorphic ventricular tachycardia (CPVT; OMIM#604772) and ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (CRDS; OMIM#115000). Although the clinical penetrance greatly varies, affected individuals may present with recurrent cardiac arrhythmias, cardiac arrest, syncope, and seizures with a mortality rate of 30-50%. Generally, gain-of-function of the RYR2 calcium channel causes CPVT by spontaneous releases of calcium ions, whereas loss of function leads to CRDS through calcium alternans. Most patients affected with CPVT or CRDS have been described to have missense variants in the RYR2 gene. The molecular mechanism of these missense variants in CPVT and CRDS is considered dominant-negative. Here we report two siblings with cardiac arrest who carried an in-frame deletion in RYR2.
