360 Retrospective Evaluation of Whole-Exome Sequencing in Puerto Ricans with Neurogenetic Complex Traits

Abstract

OBJECTIVES/GOALS: Assess the diagnostic yield and test utilization of WES in patients having complex traits. We aim to evaluate the use of the first genetic approach for the identification of primary variants that contribute to neurogenetic disease etiology and influence onset and progression in Puerto Ricans. METHODS/STUDY POPULATION: Prospective cohort of 45 Puerto Rican probands (19 months - 36 years old) with complex neurogenetic traits that underwent WES (2019 - 2021). WES was performed, including copy number variant analysis and mitochondrial genome sequencing. We evaluated several factors possibly influencing the rate of WES diagnosis including early age, consanguinity, and family history of neurogenetic diseases. In addition, we only evaluated probands rather than dyads/trios and the clinical phenotypes. Descriptive analysis was performed, including a catalog of all variants reported. Multivariate analysis was performed to estimate the statistical association between variants and phenotypes reported and adjusting for potential confounders (age, sex, family history, income, health insurance and zip code). RESULTS/ANTICIPATED RESULTS: Auspiciously, positive pathogenic findings altered the clinical management in 29% of the probands in this study. A likely genetic diagnosis was achieved in 53% of the probands including pathogenic, likely pathogenic and variants of uncertain significance. Intronic variants, copy number variants detection and mitochondrial genome was included in WES methodology. Despite these facts, a 47% of the reported WES were negative, which deserve re-analysis potentially genotype based. Multivariate analysis is expected to adjust for potential confounders to establish a genotype-phenotype correlations in neurogenetic complex traits in this Puerto Rican admixed population. DISCUSSION/SIGNIFICANCE: Clinical WES offers an alternative approach for identification of variants in patients with complex traits. WES is also applicable in genetically heterogeneous individuals when specific genetic tests are not available or unsuccessful. Variants reported contribute to understand complex neurogenetic disease in underrepresented Puerto Ricans.