Novel biallelic MEI1 variants cause female infertility characterized by multiple pronuclei formation and aberrant embryonic development.

BACKGROUND: Biallelic variants in meiosis inhibitor protein 1 (MEI1) have recently been implicated in embryonic developmental arrest. However, the genomic and transcriptomic consequences of these MEI1 variants remain only partially understood. This study aims to expand the known MEI1 variant spectrum and elucidate the molecular mechanisms by which these variants affect early embryonic development. RESULTS: Two unrelated infertile women experiencing embryonic developmental arrest were identified to carry novel biallelic MEI1 variants using whole-exome sequencing. The functional impact of these variants was characterized through a combination of in vivo and in vitro analyses. Additionally, genomic and transcriptomic sequencing was performed on embryos from one of the patients. Patient 1 carried compound heterozygous variants c.622T > C (p.Ser208Pro) and c.2647 C > T (p.Arg883Ter), while Patient 2 harbored c.3037T > G (p.Trp1013Gly) and c.2546_3525del (EX21-31del) variants. Genomic analysis of embryos demonstrated extensive chromosomal abnormalities and maternal triploidy, indicating a compromise in meiotic integrity due to biallelic MEI1 variants. Transcriptomic profiling revealed downregulation of meiotic cell cycle genes. Additionally, downregulation of epigenetic regulatory genes, particularly those involved in histone demethylation and deacetylation, was observed, suggesting abnormal transcriptional activation and genomic instability. CONCLUSIONS: Our findings broaden the spectrum of MEI1 variants associated with embryonic developmental arrest and highlight the essential role of MEI1 in oocyte meiosis and early embryonic chromosomal stability.