Maternal effect genes as risk factors for congenital heart defects

Summary: Maternal effect genes (MEGs) encode factors (e.g., RNA) in the oocyte that control embryonic development prior to activation of the embryonic genome. Over 80 mammalian MEGs have been identified, including several that have been associated with phenotypes in humans. Maternal variation in MEGs is associated with a range of adverse outcomes, which, in humans, include hydatidiform moles, zygotic cleavage failure, and offspring with multi-locus imprinting disorders. In addition, data from both animal models and humans suggest that the MEGs may be associated with structural birth defects such as congenital heart defects (CHDs). To further investigate the association between MEGs and CHDs, we conducted gene-level and gene-set analyses of known mammalian MEGs (n = 82) and two common groups of CHDs: conotruncal heart defects and left ventricular outflow tract defects. We identified 14 candidate CHD-related MEGs. These 14 MEGs include three (CDC20, KHDC3L, and TRIP13) of the 11 known human MEGs, as well as one (DNMT3A) of the eight MEGs that have been associated with structural birth defects in animal models. Our analyses add to the growing evidence that MEGs are associated with structural birth defects, in particular CHDs. Given the large proportion of individuals with structural birth defects for whom etiology of their condition is unknown, further investigations of MEGs as potential risk factors for structural birth defects are strongly warranted.