TSPYL1 is a nucleosome assembly protein (NAP) and histone chaperone that functions as a critical regulator of TGFβ signaling and cell cycle progression 1. The protein localizes to the nucleus and binds chr6 and histones, partnering with transcription factor FOXA1 and histone methyltransferase EZH2 to repress TGFBR1 expression and epithelial-mesenchymal transition 1. TSPYL1 depletion increases TGFβ signaling through elevated TGFBR1 expression and TSPYL2 protein stability, disrupting this counter-balancing regulatory axis 1. TSPYL1 deficiency causes autosomal recessive sudden infant death with dysgenesis of the testes syndrome (SIDDT), characterized by visceroautonomic dysfunction, progressive neurological abnormalities, testicular dysgenesis, and brainstem-mediated cardiorespiratory arrest 2. Pathogenic mutations result in mislocaliza of truncated protein to the Golgi, disrupting nuclear function and causing prolonged S and G2 cell cycle phases with reduced proliferation 2. TSPYL1 also regulates expression of cytochrome P450 genes including CYP3A4, with a common SNP (Pro62Ser) affecting abiraterone metabolism and prostate cancer drug response 3. While TSPYL1 mutations are associated with 46,XY disorders of sex development and male infertility cases, screening studies suggest limited diagnostic utility for idiopathic male infertility in general populations 4 5.