Understanding gene defects relative to oocyte and embryo development
Human oocyte and embryo defects are a major cause of female infertility and recurrent failure of in vitro fertilization and intracytoplasmic sperm injection. Although specific gene defects have been identified in recent years, the full extent of genetic contributions and the diagnostic yield of known pathogenic variants remains incompletely defined. The authors conducted a large multicenter study in which they performed comprehensive genetic analysis on 3,627 infertile women who had experienced at least two in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) failures due to oocyte maturation arrest, abnormal fertilization, or early embryonic arrest. Through a combined strategy of targeted TUBB8 sequencing followed by whole exome sequencing (WES), the authors evaluated 37 established causative genes and explored novel genetic contributors. Among all participants, 479 women carried pathogenic or likely pathogenic variants in known genes, resulting in a diagnostic yield of 13.2 percent. TUBB8 was the most frequently mutated gene, responsible for nearly half of all genetically diagnosed cases and associated with diverse phenotypes, including metaphase I arrest, failed fertilization, and embryonic arrest. Other important recurrently mutated genes included PATL2 and WEE2, as well as TLE6, PADI6, OOEP, and NLRP. Diagnostic yield varied across clinical subgroups, with known genes accounting for 17.5 percent of oocyte defects, 15.3 percent of fertilization failures, and 9.3 percent of embryonic arrest cases. Collectively, these genes participate in key biological pathways, such as meiotic spindle assembly, maternal mRNA regulation, meiotic recombination, protein trafficking, mitochondrial function, and oocyte-specific cell-cycle control, as well as in zona pellucida integrity. To address the unexplained cases, the authors integrated case-control burden testing with transcriptomic data from human and mouse oogenesis, identifying 123 novel candidate genes significantly enriched in affected study participants. Gene Ontology analysis demonstrated strong involvement of these candidates in cell-cycle progression, embryo development, DNA repair, protein modification, chromosome segregation, and microtubule organization. Functional validation in mouse models and cell-based assays confirmed deleterious effects of variants in five newly implicated genes—CNTD2, SPDYC, DDOST, INCENP, and MLH3—each disrupting meiotic progression, oocyte maturation, or preimplantation development. These findings expand the mechanistic understanding of female infertility, revealing previously unrecognized pathways governing early human reproduction. This study provides a comprehensive genetic landscape of human oocyte and embryo defects, establishes the utility of exome sequencing for clinical diagnosis, and underscores the importance of genetic counseling for affected women and their partners. By identifying established and novel genes underlying IVF/ICSI failure, the authors lay a foundation for future precision-guided reproductive management and highlight the need for continued investigation into noncoding, epigenetic, and paternal genetic contributions to early embryogenesis.
Chen B, Wang W, Shi J, et al. Genetic landscape of human oocyte/embryo defects. Cell Genom. doi.org/10.1016/j.xgen.2025.101012
Correspondence: Dr. Yanping Kuang at kuangyanp@126.com or Dr. Qing Sang at sangqing@fudan.edu.cn