Safeguarding the development of offspring: the role of genetic integrity of the maternal germline.
Human development begins with the fusion of sperm and oocyte, yet the maternal genome plays a far more active and essential role than traditionally appreciated. This review critically examines the influence of maternal genetic integrity on embryogenesis and offspring health, emphasizing that the maternal genome is not merely a passive donor of half the DNA, but a vital architect of early life. We explore the role of maternal effect genes (MEGs) in orchestrating early zygotic development, detailing their functions in epigenetic regulation, mitochondrial dynamics, DNA repair, and cell division. A curated reference of MEGs, spanning mouse models and human pathogenic variants, is presented to support future research and clinical diagnostics. Beyond early embryonic development, maternal genetic integrity has lasting implications for offspring well-being. Errors in DNA replication and repair machinery within the maternal germline can lead to de novo variants (DNVs)-spontaneous germline variants that can be passed on to the offspring and impact their health at different ages. We highlight an underappreciated contribution of maternally derived DNVs to a growing list of sporadic disorders and present the first comprehensive catalogue of associated diseases. We further examine DNVs compatible with multigenerational transmission, investigating how maternal age and mutational processes-such as recombination errors and epigenetic drift-influence both disease risk and evolutionary outcomes. By integrating insights from developmental biology, genomics, and reproductive medicine, this review reframes the maternal genome as a dynamic and fragile foundation upon which life depends-offering new directions for understanding fertility, sporadic disease, and intergenerational health.