Unlike the typical GOF mechanism observed in RYR2-mediated CPVT, the homozygous multiexon duplication precipitates a “calcium release channel deficiency syndrome” secondary to a profound attenuation in RYR2 transcription and RyR2 translation, which renders the CICR apparatus nearly insensitive to both catecholamine stimulation and caffeine. Here, RYR2 is linked to catecholaminergic polymorphic ventricular tachycardia.