Homozygous variant in JARID2 causes female infertility characterized by compromised blastulation efficiency.

Background: Impaired embryonic developmental competence is a critical determinant of assisted reproductive technology (ART) failure, yet current genetic diagnostics primarily address complete early embryonic arrest, leaving partial developmental defects unexplained, such as compromised blastulation efficiency (CBE). Jumonji and AT-rich interaction domain containing 2 (JARID2), encoding a chromatin-modifying factor essential for histone methylation regulation, emerges as a novel candidate in this context.

Results: We identified a homozygous JARID2 missense variant (c.899G > A, p.Arg300Gln) in a female patient exhibiting CBE under autosomal recessive inheritance. Functional studies in transiently transfected HeLa cells demonstrated preserved protein abundance and subcellular localization but significantly attenuated ERK1/2 pathway activation. Microinjection of mutant mRNA into mouse zygotes recapitulated the CBE phenotype, accompanied by diminished histone H3K27me3 levels at the 2-cell stage. Comparative transcriptomic profiling revealed conserved transcriptional alterations in both patient-derived oocytes and murine embryos, marked by downregulation of genes critical for oogenesis, maternal-to-zygotic transition, and preimplantation development.

Conclusions: These findings establish JARID2 as a maternal-effect gene governing early embryogenesis through epigenetic and ERK1/2-mediated regulatory axes, expanding the genetic diagnostic framework for ART failures and providing mechanistic insights into previously unexplained developmental defects.