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 (<i>BTG4</i>, <i>ZFP36L2</i>, <i>ZAR1</i>), subcortical maternal complex (<i>TLE6</i>, <i>PADI6</i>, <i>OOEP</i>, <i>NLRP2</i>, <i>NLRP5</i>, <i>NLRP7</i>, <i>KHDC3L</i>), DNA double-strand break formation and homologous recombination (<i>REC114</i>, <i>TOP6BL</i>, <i>MEI1</i>, <i>MEI4</i>, <i>TRIP13</i>), spindle assembly (<i>TUBB8</i> and <i>TUBA4A</i>) and cell cycle and checkpoints (<i>FBXO43</i>, <i>MOS</i>, <i>CHEK1</i>, <i>TRIP13</i>, <i>CDC20</i>), as well as nuclear transport and translational regulation (<i>KPNA7</i>, <i>DDOST</i>). 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.