We propose that the RYR2 mutation is a potentially novel neurocardiac calcium channelopathy that may manifest with either CPVT or GGE depending on selective involvement of RYR2 receptors expressed in the heart or in the brain.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy usually caused by gain-of-function mutations ryanodine receptor type-2 (RyR2).
Targeted postmortem genetic testing of the 4 major channelopathy-susceptibility genes (KCNQ1, KCNH2, SCN5A, and RYR2) have yielded putative pathogenic mutations in ≤30% of autopsy-negative sudden unexplained death in the young (SUDY) cases with highest yields derived from the subset of exertion-related SUDY.
Adhering to the recommendations of including molecular diagnostics of cardiac channelopathies in SUD investigation, the Molecular Genetics Laboratory of the New York City (NYC) Office of Chief Medical Examiner (OCME) has been routinely testing for six major channelopathy genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, and RyR2) since 2008.
Functional characterisation of these RyR2 Ca(2+) channelopathies suggests that mutations alter the ability of RyR2 to sense its intracellular environment, and that channel modulation via covalent modification, Ca(2+)- and Mg(2+)-dependent regulation and structural feedback mechanisms are catastrophically disturbed.