Comment on “Genetic Architecture and Phenotypic Diversity of Oocyte and Early Embryo Competence Defects in Female Infertility”

Infertility is currently estimated to affect 12.6% to 17.5% of couples globally, and with this, the use of in vitro fertilization (IVF) has become widely used and performed frequently (more than 3 million cycles annually). Though it is widely used, the current live birth rate of IVF remains low, at 30% to 40% per cycle. IVF success depends heavily on oocyte quality, and low-quality oocytes can manifest with abnormalities in oocyte or early embryo development. Research classifications of these differences have been inconsistent, and no underlying causes have been identified. This article proposes the term “oocyte and early embryo competence defects” (OECD) to describe recurrent failures in IVF with no transferable embryos due to oocyte quality. Genetic connections to OECD have been described, but not consistently. This study also aims to assess the largest OECD cohort to date for a pathogenic variant spectrum of genes to identify causal genes for OECD. This study recruited patients from a single IVF clinic who had experienced recurrent failures of IVF cycles that were attributed to OECD. Exclusion criteria were patients with incomplete information and patients over the age of 40, with a history of live birth, and other infertility causes. Whole-exome sequencing (WES) or whole-genome sequencing (WGS) was performed for all patients. Final analysis included 2140 patients with OECD and 2424 fertile controls with a history of spontaneous conception and live birth. The OECD patients were classified into 6 subtypes, including empty follicle (EF), oocyte maturation arrest (MA), fertilization failure (FF), zygote arrest (ZA), early embryonic arrest (EA), and mixed phenotype (MIX). Most patients showed a consistent phenotype over multiple cycles, with EA being the most prevalent. WES data showed 183 pathogenic or likely pathogenic (P/LP) variants across 28 genes. Of the variants identified, 80 were loss of function (LoF, 43.7%), 94 were missense (51.4%), and 9 were insertions or deletions (indels, 4.9%). The most frequent gene to have variations identified was TUBB8 , and all subtypes showed variants in this gene, with the exception of EF. Variants in TBPL2 and TRIP13 were detected mostly in MA, WEE2, and ASTL variants were mostly associated with FF, and CHEK1 was associated with ZA. The EA and MIX groups showed a larger variation of affected genes. A total of 238 patients were genetically diagnosed with one of the 28 genes examined, with the highest genetic diagnostic rates exhibited in the EF and ZA groups. WES data were then screened for other nonestablished genes that may be associated with causative variants for OECD. From this analysis, CENPH and MLH3 were identified as biallelic and potentially causative. All patients identified with variants in these genes were in the EA subgroup, where no blastocysts were obtained. Mouse models were subsequently used to assess the effect of these genes in embryos, and results consistently showed failure of blastocyst formation. When 11 additional genes were included in the genetic diagnostic rate, a rate of 12.8% was achieved. These results indicate that it is important to consider the genetic and phenotypic heterogeneity of OECD and suggest that rarer subtypes of the condition may have a greater genetic contribution. Those that showed less genetic involvement may yet show an association with multiple gene variants interacting with one another that result in a pathologic phenotype. Future research should validate the findings in the newly identified genes presented in this study, as well as further replication in larger samples. (Summarized from Zhang C, Zheng W, Zhang H, et al. Genetic architecture and phenotypic diversity of oocyte and early embryo competence defects in female infertility. Nat Med . 2026;32(1):72-81. doi: https://10.1038/s41591-025-04001-1)