Causes for SUDEP are unknown. Although heart arrhythmias are suspected, this has not been definitively demonstrated. Progress on determining causes, and thereby developing means to identify at-risk patients or preventing occurrence, has been impeded by the lack of animal models. We propose a novel hypothesis that mutations in broadly expressed ion channel modulators could affect brain channels (causing seizures) and also alter cardiac channels, thereby increasing susceptibility to life-threatening arrhythmias. We propose to test this hypothesis with new animal models, leading to the rational discovery of SUDEP candidate genes and development of diagnostic tools for identifying susceptible individuals.