SUMMARY Hypertrophic cardiomyopathy (HCM) affects up to 1:200 individuals and is a common cause of sudden cardiac death. Guidelines recommend genetic testing in HCM probands to help establish diagnosis, inform risk stratification, and identify at-risk relatives. However, causal variants are identified in fewer than half of patients, many tests return variants of uncertain significance (VUS), and genotype-phenotype associations of known genes are insufficiently characterized to inform medical management. In this proposal we address 4 gaps in HCM research: 1) Most data are from individuals of European ancestry referred for genetic testing, creating bias in estimates of the contribution, penetrance, and phenotype in the broader clinical and community population. 2) Established HCM genes have insufficient genotype-phenotype data to inform gene-specific clinical management. 3) The evidence for most candidate genes is equivocal due to lack of study in cohorts sufficiently large to evaluate pathogenicity. 4) Some disease loci likely remain undiscovered because GWAS and linkage approaches used in prior studies are not well-powered for diseases, such as HCM, with variable age of onset, both high genetic and allelic heterogeneity, and incomplete penetrance. We will address these fundamental knowledge gaps using innovative genetic methods and a novel, large-scale HCM research platform that includes harmonized phenotypic, genotyping, sequencing, and identity-by-descent (IBD) data from six large biobanks comprising ~1.5M participants and >5,000 HCM cases. Specifically, we propose to use rare variant and IBD-based methods to: Aim 1) Define the contribution and phenotypic manifestations of established disease genes in multiple diverse, non-referral HCM populations; Aim 2) Assess the pathogenicity of candidate HCM genes with equivocal evidence and establish a novel platform to evaluate VUS in established genes; and Aim 3) Discover novel HCM loci via IBD mapping and rare variant association within and across biobanks at scale. To balance the innovation of these aims, we present compelling preliminary data demonstrating the feasibility of our approaches which identified a cluster of distantly related individuals harboring a common pathogenic variant in a Mendelian cardiomyopathy gene. We anticipate these analyses will substantially expand our understanding of the genetic factors underlying HCM risk and their clinical manifestations. Once established, our platform will support future clinical and genetic research and advance the long-term goal of implementing targeted interventions at the clinic and population level to reduce the burden of HCM for all patients.