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We investigated the incidence of four Lysosomal Storage Disorders (LSDs) in a cohort of mostly urban-dwelling African Americans, compared to previous work primarily in Caucasians (and Ashkenazi Jews). LSDs are inherited genetic disorders that result in the functional absence or deficiency of specific lysosomal enzymes resulting in a range of clinical symptoms manifesting in various organ systems. To highlight diagnostic challenges originating from ambiguous clinical manifestations, we initiated a large scale screening for 'treatable forms' of LSDs in 5000 patients seeking healthcare for various health concerns. Of these, 85% reported as African American, 10% Hispanic, and 5% Caucasian or other. Dried blood spots were prepared from peripheral blood samples and fluorometric enzyme assays performed for β-glucosidase (Gaucher disease), α-galactosidase (Fabry disease), α-glucosidase (Pompe disease), and β-galactosidase (MPS IV B) enzymes. On samples which showed significantly lower enzyme activities, molecular analysis was performed using targeted sequencing. After two rounds of screening, we confirmed undetectable activity for β-glucosidase in 1 subject α-galactosidase in 3 subjects β-galactosidase in 1 subject and α-glucosidase in 5 subjects. In addition, approximately 0.05-0.1% showed significantly reduced enzyme activity, likely indicating carrier status. These samples are being screened using Next-Gen Sequencing and preliminary results highlight higher incidence rates for abnormal enzyme levels and pathogenic mutations in the target population compared to previously published LSD screenings. The findings could be because the patient cohort was already under clinical care thus increasing the likelihood of a disease phenotype or due to ancestry-based genotype and phenotype variations. It is highly likely that variations in genomics and resultant biochemical cascades contribute to health and disease. The study highlights the importance of such large scale screenings in minority groups traditionally not associated with a high incidence of LSDs. The study is partially funded by Shire (IIR-USA-000892), Pfizer (WI194030) & NCATS/NIH (#UL1-TR001409). [ABSTRACT FROM AUTHOR]