Genetic mechanisms of fertilization failure and early embryonic arrest: a comprehensive review.

This article comprehensively reviews the genetic and epigenetic mechanisms underlying fertilization failure (FF), zygotic cleavage failure (ZCF), and early embryonic arrest (EEA) in human infertility. It highlights key gene mutations affecting male factors—such as PLCZ1, ACTL7A, ACTL9, IQCN, CATSPER3, and KCNU1—and female factors—including WEE2, TUBB8, zona pellucida glycoproteins (ZP1–3), ASTL, CDC20, and components of the subcortical maternal complex (SCMC) like OOEP, KHDC3L, TLE6, PADI6, NLRP2/5/7—that disrupt processes from sperm capacitation and oocyte activation to embryonic genome activation (EGA). The review also discusses chromosomal abnormalities, mitochondrial DNA defects, and epigenetic modifications (DNA methylation, histone modifications, and non-coding RNAs) as contributors to reproductive failure. Clinical implications include the use of assisted reproductive technologies (ART) such as intracytoplasmic sperm injection (ICSI), assisted oocyte activation (AOA), and mitochondrial transfer, with gene-specific interventions proposed where possible; however, some genetic defects currently lack effective treatments, underscoring the need for further research to improve diagnosis and personalized management of infertility.