Sudden death in the young (SDY) is a tragic event, with devastating consequences for the family who must endure both the unexpected loss of their child and the possibility of harboring a familial disorder that threatens the health and survival of the remaining members. Due to lack of evidence, there is little consensus within the scientific community around the best method for preventing SDY. Thus, the National Heart, Lung, and Blood Institute (NHLBI), National Institute of Neurologic Disorders and Stroke (NINDS) and Centers for Disease Control and Prevention (CDC) have invested extensively in the SDY Case Registry by acquiring detailed clinical information and archiving DNA samples from SDY cases across the United States, with the goal of defining the genomic and mechanistic basis for SDY. We propose to establish the Utah SDY Center as an integral partner of the SDY Registry, by providing unparalleled bioinformatics, genomics and clinical expertise, resources, and an infrastructure for collaboration to accomplish the Registry's goals. Our proposal addresses several critical barriers in the field of SDY research: 1) standard genetic testing fails to identify a molecular cause in the majority of autopsy-negative SDY; 2) current strategies do not validate the functionality of identified variants; and 3) a comprehensive family cardiac evaluation is inconsistently performed despite Class I expert consensus recommendations. We propose to overcome these barriers by achieving the following Aims: Specific Aim 1: Provide the SDY Case Registry with the bioinformatics expertise that will enable the discovery of the genomic basis for autopsy-negative SDY, using whole-exome/genome sequencing. Specific Aim 2: Characterize novel SDY disease genes, alleles and disease mechanisms, using cell- and model organism-based assays. Specific Aim 3: Integrate our clinical expertise in SDY to phenotype, genotype, risk-stratify and counsel surviving family members. The Utah SDY Center's multi-disciplinary research plan will allow us to discover, validate and characterize new sudden death genes, alleles and mechanisms at a scale and resolution not previously possible. By partnering with other SDY Case Registry Centers, the Utah Center will promote a mechanistic understanding of SDY and thus establish the foundation for future screening strategies and preventative measures.