Ballelic Variants of TTC ‐Related Genes Cause Asthenoteratozoospermia With Favorable Clinical Outcomes After ICSI

BACKGROUND: Male infertility is a complex, multifactorial disorder that affects ∼7% of men worldwide. Variants in DNAH and CFAP genes are well-established causes of asthenoteratozoospermia, but the contribution of TTC-family genes (TTC12, TTC21A, TTC29) to sperm dysfunction and ICSI outcome remains poorly documented. OBJECTIVES: To investigate the genetic and clinical implications of TTC gene variants in men with asthenoteratozoospermia and to evaluate the ICSI outcomes of affected individuals. MATERIALS AND METHODS: We performed whole-exome sequencing and bioinformatic filtering in 843 men with asthenoteratozoospermia. Candidate variants were validated by Sanger sequencing, and the effects on protein expression were assessed using western blotting and immunofluorescence. Sperm morphology and ultrastructure were examined by light and transmission electron microscopy. Clinical outcomes were evaluated following ICSI treatment, including a total of 18 TTC-variant patients and DNAH1-variant men. RESULTS: Thirteen TTC variants in 11 unrelated patients (1.3%) were identified in this cohort, including two homozygous TTC12 variants, six homozygous plus two compound-heterozygous TTC21A variants, and one homozygous TTC29 variants. Variants induced markedly reduced TTC proteins expression and disorganized axonemes and peri-axonemal structures. Clinical data from ICSI cycles demonstrated that fertilization could be achieved, importantly the first reported live birth for TTC21A variants, although blastocyst rates were lower than in DNAH1-mutated controls. CONCLUSION: This study not only expanded the genotype-phenotype spectrum of variations in the TTC gene family, but also built a bridge between molecular genetics and clinical application, demonstrating the translational path from gene discovery to effective treatment.