Sudden death in the young (SDY) is a critical public health issue with significant knowledge gaps, specifically in the epidemiology and etiology of SDY in the United States. In a proportion of unexplained SDY cases, the etiology is a genetic arrhythmia syndrome caused by mutations in genes encoding cardiac ion channels or regulatory proteins. Post-mortem genetic testing has suggested the cause of death in 10-35% of autopsy- negative SD cases. Occasionally, mutations are identified with clear-cut pathologic significance, but a major challenge to the field is that many identified mutations are novel or uncharacterized, and pathogenicity is difficult to determine. The NIH in collaboration with the CDC has established a prospective, population-based SDY registry, with collection of DNA samples for cases with no definitive cause on autopsy, allowing post- mortem genetic investigation. The goals of this research program are to address knowledge gaps in unexplained SDY with a multifaceted approach which includes sequencing ion channel and high-priority candidate genes in SDY cases and controls, in vitro assessment of putative pathogenic mutations, and systematic clinical evaluation for family members of SDY victims (Specific Aim 1). Control samples are available from a very large (> 200,000 samples) electronic medical record-linked biobank in place at our institution. We also propose expansion of the SDY biorepository to include tissue samples from SDY victims and investigating developmental regulation of ion channel expression as a factor in infant SD (Specific Aim 2). The investigative team has established collaborations with one of the SDY Case registry funded agencies (Tennessee Department of Health) and the regional Medical Examiner's office in order to carry out the proposed studies. Accomplishing these Aims will: allow return of clinically-actionable results to families by investigators with expertise in interpretation of ion channel variants and clinical car of channelopathies; enhance the SDY biorepository with a tissue bank and a DNA biorepository from a large well-phenotyped control cohort; and investigate potential novel mechanisms underlying SDY.