Genetic Mutations and Non-Genomic Dysregulation in Human Preimplantation Embryo Arrest

Human preimplantation embryo arrest (PREMBA) represents a significant clinical hurdle in assisted reproductive technology (ART), in which approximately 10% of in vitro fertilized (IVF) embryos arrest at the cleavage stages. Whole-exome sequencing (WES) studies have discovered numerous genetic mutations associated with preimplantation embryo arrest. These mutations often disrupt critical biological milestones such as maternal mRNA clearance (BTG4, ZFP36L2, ZAR1), subcortical maternal complex (TLE6, PADI6, OOEP, NLRP2, NLRP5, NLRP7, KHDC3L), DNA double-strand break formation and homologous recombination (REC114, TOP6BL, MEI1, MEI4, TRIP13), spindle assembly (TUBB8 and TUBA4A) and cell cycle and checkpoints (FBXO43, MOS, CHEK1, TRIP13, CDC20), as well as nuclear transport and translational regulation (KPNA7, DDOST). However, the cause of most clinical cases remains genetically unexplained. Studies investigating these unexplained arrests have uncovered widespread multi-omics abnormalities, including transcriptional arrest, DNA hypermethylation, higher chromatin accessibility, aberrant histone modification, chromosomal aneuploidy and senescent-like states. This review provides a comprehensive overview of the molecular mechanisms underlying PREMBA, categorized into those that are attributable to known genetic mutations and those with unexplained reasons.