SUMMARY / ABSTRACT – Inherent Biosciences Dr. Dolores Lamb from the Weill Cornell Medicine (WCM) has discovered a novel epi- genetic source of male-infertility that has been shown to be the most common genetic source of sperm impairment in men suffering for non-obstructive azoospermia (NOA). Inherent Biosciences in collaboration with WCM proposes the development of a cost-effective commercial diagnostic for use in genetic testing of incoming patients at the Department of Urology at WCM. Prior to this discovery, Klinefelter’s syndrome and Y chromosome microdeletions were the two most prevalent genetic causes of male infertility. Klinefelter’s syndrome and Y chromosome microdeletions account for 11% and 8% respectively in azoospermic men. According to the current AUA/ ASRM Guidelines, genetic testing for both Klinefelter’s syndrome and Y-chromosome microdeletion is recommended for all men with severe oligospermia or azoospermia to clarify etiology of male infertility prior to treatment (market size of 12.2 million men worldwide). Work from the Lamb Lab over the last 20 years has identified epigenetic mutations in men at specific sites within the DNA/mismatch repair genes (MMRs) accounting for 17% of men with dysfunctional sperm production (twice as frequent as Y chromosome microdeletions). Once commercially available and clinically validated in the Department of Urology at WCM, we believe this test will become one of the ASRM/AUA recommended genetic tests for all men with severe oligospermia or azoospermia. Phase 1 of the SBIR study will focus on 1) developing a highly accurate and cost-effective targeted sequencing assay for analysis of the novel epigenetic mutations identified by Dr. Lamb and 2) validating the assay in a CAP/CLIA laboratory using 200 samples from WCM. Phase 2 of this proposal will be dedicated to the development and commercialization of an LDT assay for use on all NOA patients treated at WCM.