PROJECT SUMMARY The odyssey to a diagnosis for patients with hereditary TTR amyloidosis (hATTR) often lasts years because the signs and symptoms are non-specific. Meanwhile, patients can progress to advanced heart disease (cardiac amyloidosis) and nerve disease (polyneuropathy). A common pathogenic TTR variant impacting African American (4%) and Hispanic/Latino (1%) patients, V142I, confers particularly high risk for cardiac amyloidosis, but diagnostic delays keep these groups at the margins of care. Novel therapies are now available to delay hATTR progression; however, they cannot reverse the disease. For this reason, it is imperative to diagnose hATTR at the earliest possible stages, when these therapies are likely to be most beneficial. Because the gold standard for non-invasive diagnosis of hATTR-related cardiac amyloidosis, nuclear scintigraphy, involves exposure to ionizing radiation and the sensitivity in asymptomatic patients is unknown, widespread screening by this method is not yet justified. Traditional phenotype-first studies have identified non-cardiac red flag signs and symptoms that herald future heart disease, but the complete phenotypic spectrum and natural history of hATTR are not well understood, particularly in individuals at high genetic risk. To date, large diverse cohorts of individuals with pathogenic TTR variants (TTR+) have not been extensively studied to understand the full range of clinical features of hATTR. We propose a genotype-first study of predominantly African American and Hispanic/Latino TTR+ individuals from the electronic health record (EHR)-linked BioMe Biobank in New York City. First, we will perform retrospective deep phenotyping using EHRs to characterize the scope and develop a timeline of cardiac and non-cardiac features of hATTR, and estimate age-dependent penetrance. We will perform a well-powered phenome-wide association study, in collaboration with other biobanks, to identify novel health traits associated with V142I. Clinical characteristics found to be enriched in TTR+ individuals will be accrued into a phenotype risk score to help identify patients at risk for hATTR in health systems. In addition, we will conduct a prospective study to generate evidence informing guidelines for optimal mode and timing of cardiac imaging surveillance in high-risk TTR+ individuals across adulthood. We will recruit 100 TTR+ individuals from BioMe into a multimodal cardiac imaging study using gold standard and cutting-edge experimental imaging approaches. Through these endeavors, we will delineate a timeline of anticipatory systemic and cardiac imaging signatures unique to individuals at high genetic risk for hATTR. The results will empower clinicians to recognize the disease at its earliest stages so patients may maximally benefit from therapy. We posit that although hATTR is currently grossly underdiagnosed in U.S. minority patients, it is in fact amenable to earlier detection through discovery of prescient signs a...