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

Biallelic MEI1 mutations found in 1.9% of azoospermic men; surgical sperm retrieval failed 12/12 times

Journal: Journal of Assisted Reproduction and Genetics | Published: 2026-02-18 | Type: Journal Article | PMID: 41706353 Authors: Tan Chen, Wang Tiantian, Tu Chaofeng et al. (NHC Key Laboratory of Human Stem Cell and Reproductive Engineering, Xiangya School of Basic Medical Sciences; Reproductive & Genetic Hospital of CITIC-Xiangya, Hunan) Funding/COI: National Key Research and Development Program of China; Graduate Research and Innovation Projects of Central South University. No competing interests declared.

Summary

MEI1 encodes a protein required for the meiotic double-strand DNA breaks that initiate chromosome recombination during spermatogenesis. Biallelic loss-of-function variants block sperm production entirely — and in every one of the 12 men with these mutations who underwent micro-TESE, surgeons retrieved zero sperm. At 1.9% of a 626-patient azoospermia cohort, MEI1 is shaping up as one of the more common single-gene causes of complete spermatogenic failure yet characterized.

Claims

• Biallelic pathogenic MEI1 variants identified in 1.9% (12/626) of non-obstructive azoospermia (NOA) patients
• Heterozygous MEI1 variants found in 0.17% (28/1,607) of a broader idiopathic male infertility validation cohort (626 NOA, 799 severe oligoasthenospermia, 182 terato/asthenozoospermia)
• Micro-TESE surgical sperm retrieval: 0/12 success rate in biallelic carriers
• Mutations disrupted binding to meiotic proteins ANKRD31, IHO1, REC114, and MEI4 in co-immunoprecipitation assays
• Authors propose MEI1 as a preoperative genetic marker to identify men for whom micro-TESE will be futile

Study Quality

Two-cohort design: 626 NOA patients screened for biallelic mutations, then a separate 1,607-case idiopathic infertility cohort screened for heterozygous variants — a reasonable validation architecture. Functional mechanistic work via co-immunoprecipitation demonstrates disrupted protein-protein interactions for mutant MEI1, grounding the pathogenicity calls in biology rather than just computational prediction. The clinical outcome data (micro-TESE results) is the study's sharpest contribution: 12/12 surgical failures in biallelic carriers is a clinically striking number, even if the absolute denominator is small.

The entire cohort is Chinese, recruited from a single specialty center in Hunan province. Prevalence figures from clinic-recruited azoospermia patients will overstate population-level rates. The 1.9% figure applies to men already presenting at a reproductive genetics center, not to azoospermic men broadly.

Red Flags

• Single ethnicity, single center: prevalence estimates are not population-representative and may not generalize to non-East-Asian cohorts
• n=12 biallelic carriers — the 100% micro-TESE failure rate is striking but rests on a thin denominator; one outlier would shift the picture meaningfully
• No functional rescue experiments (reintroduction of wild-type MEI1 in a model system); mechanistic causality depends entirely on co-IP disruption
• Clinical significance of heterozygous variants (0.17% of the infertility cohort) is not established — incomplete penetrance and carrier status are not addressed
• Clinic-enriched NOA cohort inflates apparent gene prevalence relative to unselected infertile men

Strengths

• Largest MEI1 screening cohort reported to date, across two independent patient groups
• Hard clinical endpoint (micro-TESE outcome) directly validates the diagnostic claim
• Functional co-IP work with four binding partners strengthens pathogenicity argument
• Government-funded, no industry conflict of interest
• Ethics approvals and informed consent documented

Verdict

The core claim — that preoperative MEI1 sequencing could identify the subset of azoospermic men for whom micro-TESE is surgically futile — is credible and clinically relevant, and the study design is honest enough to support it cautiously. The limitations are real: 12 cases is not a large series, and single-center Han Chinese recruitment means nobody should apply these prevalence numbers to a European or African cohort without replication. The mechanistic co-IP work is solid but stops short of rescue experiments. This paper earns attention from genetic counselors and andrologists; it does not yet establish a universal screening standard.