TDRD9 is an ATP-dependent RNA helicase essential for male germline integrity and spermatogenesis. It functions within the piRNA (piwi-interacting RNA) pathway to silence transposable elements, particularly Line-1 retrotransposons, through piRNA-mediated DNA methylation and heterochromatin formation 1. TDRD9 acts as a nuclear effector downstream of piRNA biogenesis, forming complexes with MIWI2 in germline processing bodies to enforce transposon repression during meiosis 1. Pathogenic variants in TDRD9 cause male infertility with azoospermia or oligozoospermia. Compound heterozygous and homozygous loss-of-function variants—including frameshift mutations, splicing defects, and missense changes—have been identified in infertile men with meiotic arrest or incomplete spermatogenesis 2, 3, 4. Notably, all individuals harboring meiotic-pathway gene defects including TDRD9 mutations showed unsuccessful sperm retrieval 2, suggesting that genetic diagnosis could identify candidates unlikely to benefit from testicular sperm extraction. TDRD9 mutations also cause globozoospermia, a morphological sperm defect involving abnormal head structure 5. Reduced TDRD9 expression correlates with multiple forms of non-obstructive azoospermia 6, underscoring its critical role in human spermatogenesis.