Malignant hyperthermia is a pharmacogenetic disorder associated with mutations in Ca(2+) regulatory proteins. It manifests as a hypermetabolic crisis triggered by commonly used anesthetics. Malignant hyperthermia susceptibility is a dominantly inherited predisposition to malignant hyperthermia that can be diagnosed by using caffeine/halothane contracture tests. In a multigenerational North American family with a severe form of malignant hyperthermia that has caused four deaths, a novel RYR1 A2350T missense mutation was identified in all individuals testing positive for malignant hyperthermia susceptibility. The same A2350T mutation was identified in an Argentinean family with two known fatal MH reactions. Functional analysis in HEK-293 cells revealed an altered Ca(2+) dependence and increased caffeine sensitivity of the expressed mutant protein thus confirming the pathogenic potential of the RYR1 A2350T mutation.