TEX15 variants in male infertility: a real-world cohort study

To evaluate the clinical phenotype and interpretability of TEX15 gene variants in a real-world cohort of patients with primary testicular disease.

We conducted a retrospective single-center study including patients with primary testicular dysfunction. Patients carrying isolated TEX15 gene variants (n = 7) were compared with a pathological control group (n = 145) from a cohort of infertile patients with primary testicular failure without identifiable genetic alterations. Clinical, hormonal, and seminal parameters were analyzed using non-parametric tests. Effect size was estimated using Cliff's delta.

TEX15 gene variants were identified in 0.9% of the cohort. No pathogenic biallelic variants were identified. Compared to pathological controls, TEX15-positive patients showed lower FSH concentrations (p = 0.031), higher sperm concentration (p = 0.002), and higher total sperm count (p = 0.002). Azoospermia was absent among TEX15 cases but present in 62.1% of controls (p = 0.002). No significant differences were observed in LH, testosterone levels, estradiol concentrations, or testicular volume. Sensitivity analyses excluding biologically atypical subjects attenuated most observed differences. Overall, TEX15-positive patients showed heterogeneous clinical presentations with limited phenotypic specificity compared to other forms of primary testicular dysfunction.

Our findings indicate that TEX15 gene variants, particularly in heterozygous state, have limited clinical interpretability and do not define a clearly distinguishable clinical phenotype. These findings suggest that isolated TEX15 variants, particularly in heterozygous state, should be interpreted cautiously in routine male infertility diagnostics pending further functional validation.