Maternal effect genes: Update and review of evidence for a link with birth defects

Summary Maternal effect genes (MEGs) encode factors (e.g., RNA) that are present in the oocyte and required for early embryonic development. Hence, while these genes and gene products are of maternal origin, their phenotypic consequences result from effects on the embryo. The first mammalian MEGs were identified in the mouse in 2000 and were associated with early embryonic loss in the offspring of homozygous null females. In humans, the first MEG was identified in 2006, in women who had experienced a range of adverse reproductive outcomes, including hydatidiform moles, spontaneous abortions, and stillbirths. Over 80 mammalian MEGs have subsequently been identified, including several that have been associated with phenotypes in humans. In general, pathogenic variants in MEGs or the absence of MEG products are associated with a spectrum of adverse outcomes, which in humans range from zygotic cleavage failure to offspring with multi-locus imprinting disorders. Although less established, there is also evidence that MEGs are associated with structural birth defects (e.g., craniofacial malformations, congenital heart defects). This review provides an updated summary of mammalian MEGs reported in the literature through early 2021, as well as an overview of the evidence for a link between MEGs and structural birth defects.