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

Abstract

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.

The Centriole’s Role in Miscarriages

“…In this perspective, we will provide insight into the elusive reproductive functions of centrioles and offer a potential explanation as to why mice evolved centriole-independent reproduction. It is important to note that many other mechanisms function in the zygote and play a critical role in assuring normal embryonic development ( Bury et al, 2016 ; Masset et al, 2021 ; Mitchell, 2022 ). Furthermore, in addition to the centrioles, there are many other differences between mice and humans during early embryogenesis, including the timing of embryonic genome activation ( Niakan et al, 2012 ), and the role of the master regulator of cell pluripotency ( Daigneault et al, 2018 ).…”

Maternal effect genes as risk factors for congenital heart defects

“… 2 , 3 , 4 , 5 Although less is known about the role of MEGs in the development of mammals, the first mammalian MEG was reported in 2000, 6 and over 80 mammalian MEGs have subsequently been identified. 7 Most evidence implicating these genes as MEGs comes from animal studies. However, the first human MEG was reported in 2006, 8 and potentially damaging variants in at least 10 additional genes have been identified in women with a range of adverse post-fertilization reproductive outcomes, including zygotic cleavage failure, recurrent pregnancy loss, and hydatidiform moles.…”

“… 9 , 10 , 11 , 12 The known mammalian MEGs are enriched for genes that map to biological pathways and processes (e.g., chromatin, imprinting, and methylation) that are essential for early embryogenesis and set the stage for subsequent developmental events. 7 …”

“… 15 Although studies of MEGs have not routinely included the evaluation of structural birth defects, eight MEGs ( Dnmt1 , Dnmt3a , Dnmt3l , Kdm1b , Nlrp2 , Tet3 , Trim28 , and Zfp57 ; approximately 10% of the known mammalian MEGs), have been associated with birth defects, including congenital heart defects (CHDs), in animal models. 7 In addition, in our genome-wide analysis to identify maternal genes associated with conotruncal heart defects, several of the most significant associations involved genes that have been implicated as MEGs. 17 Based on this observation, we compiled a list of MEGs from review articles published between 2014 and 2016, 6 , 18 , 19 and conducted a post hoc analysis to determine whether associations with p < 0.05 in our analyses were enriched for the genes on this list.…”

“…Consequently, we completed a comprehensive review of the literature and systematically curated an up-to-date list of mammalian MEGs. 7 Building on this work, we then undertook a new study to assess the hypothesis that mammalian MEGs (either individually or as a set) are associated with CHDs.…”