Reassessing TEX11 Variants in Male Infertility: A Systematic Review of Pathogenicity, Testicular Histopathology, and Implications for Sperm Retrieval

Background/objectives: TEX11 variants are an established cause of male infertility, particularly non-obstructive azoospermia (NOA) with meiotic arrest. However, the pathogenicity of many reported variants and their implications for sperm retrieval remain uncertain. We aimed to reassess TEX11 variant pathogenicity and evaluate evidence relevant to testicular sperm extraction (TESE). Methods: We systematically reassessed reported TEX11 variants by integrating clinical phenotype, testicular histology, computational predictions, functional evidence, and structural modelling of TEX11 interactions with its meiotic partners. Available sperm-retrieval data were also reviewed to assess their relevance for testicular sperm extraction (TESE). Results: Sixty-one unique variants were identified. After reassessment, 22 (36.1%) were classified as pathogenic or likely pathogenic, 27 (44.3%) as benign or likely benign, and 12 (19.7%) as variants of uncertain significance. Truncating variants accounted for most pathogenic variants and were predominantly associated with NOA and meiotic arrest. Among carriers with available histological data, meiotic arrest was the predominant finding (36/45, 80.0%), whereas individually documented sperm retrieval outcomes were limited, precluding reliable variant-specific predictions of TESE success or failure. Conclusions: These findings emphasize the distinction between molecular pathogenicity, histological impairment, and sperm retrieval prognosis. Current evidence does not support using TEX11 genotype alone to contraindicate TESE.