A common cause of non-obstructive azoospermia: biallelic MEI1 variants and implications for infertility diagnostics.

Infertility affects about 15% of couples globally, with genetic factors contributing significantly. Advances in genomic technologies have led to the discovery of genes like MEI1, which play a crucial role in meiosis. However, the population prevalence and pathological mechanisms of human MEI1 variants remains poorly defined. To elucidate the contribution of MEI1 to spermatogenic failure, initial screening for biallelic mutations was conducted in 626 non-obstructive azoospermia (NOA) patients, followed by targeted screening for heterozygous variants in a validation cohort comprising 1,607 well-characterized idiopathic male infertility cases (626 NOA, 799 severe oligoasthenospermia, and 182 terato/asthenozoospermia). Here, we identify MEI1 as a prominent gene associated with non-obstructive azoospermia (NOA), with biallelic pathogenic variants in MEI1 were identified in 12 individuals (1.9%, 12/626). Furthermore, heterozygous MEI1 mutations were identified in 28 patients (0.17%, 28/1607) from the broader infertility screening cohort implicate MEI1 in a wider phenotypic spectrum, broadening its clinical relevance. Critically, micro-TESE uniformly showed no sperm retrieval in individuals carrying biallelic MEI1 mutations, underscoring the imperative for preemptive genetic screening to avoid unnecessary surgical interventions. Mechanistically, these mutations disrupted interactions with key meiotic proteins (ANKRD31, IHO1, REC114, MEI4) in co-immunoprecipitation assays. These results not only elucidate its essential function in meiosis and DSB formation but also support its potential as a molecular marker for non-invasive diagnosis.