RYR2 and colorectal carcinoma: Indeed, rather than a GOF in calcium release through hyperactive or hyperreactive (i.e., “leaky”) RyR2 calcium release channels as typically observed in CPVT1, our patient-specific homozygous RYR2 duplication iPSC-CMs displayed a cellular phenotype of CRC deficiency, as evident by severely reduced RyR2 protein levels, essentially no Ca2+ responsiveness to ISO, and dramatically reduced Ca2+ responsiveness to caffeine (RyR2 agonist).