Birth defects are the leading cause of death in the first year of life, and a significant cause of morbidity and mortality in all age groups. Structural malformations, such as congenital heart defects (CHDs), orofacial clefts (OFC) and congenital diaphragmatic hernia (DH), comprise a significant portion of all birth defects: With a birth prevalence of approximately 1%, CHDs alone account for up to a third of all birth defects. Since structural malformations cannot be cured, primary prevention is an important goal. Progress towards prevention is, however, impeded by gaps in knowledge about the causes of structural malformations. While studies of inherited and de novo variants have begun to define the role of the embryonic genotype, much remains unknown about the causes of these conditions. We believe that studies of the maternal genotype will help to fill this knowledge gap. A role for the maternal genotype in determining the risk of structural malformations is supported by epidemiologic evidence that genetically-mediated, maternal phenotypes are risk factors for structural malformations. For example, maternal obesity is associated with increased risk of several malformations (i.e. it is non-specific), including CHDs, OFC and DH. Further, studies have identified associations between structural malformations and the maternal genotype for genes involved in folate metabolism (e.g. MTHFR) and for obesity and diabetes-related genes (e.g. UCP2). In addition, our preliminary data provide novel evidence that maternal effect genes (MEGs), which encode the maternal transcripts and proteins in the oocyte that direct development prior to the activation of the embryonic genome, are also related to the risk of structural malformations. Our long- term goal is to identify the causes of structural malformations and to translate this knowledge into prevention strategies. Our objective in this study is to leverage the resources provided by the Gabriella Miller Kid's First initiative to identify maternal genes associated with structural malformations. Our working hypotheses for the proposed studies are: 1. Maternal genotypes for MEG variants (common and rare) are associated with structural malformations; 2. There are additional, as yet unidentified, genes that are associated with risk of structural malformations via the maternal genotype; and 3. The effects of the maternal genotype are non-specific and, therefore, contribute to the risk of multiple different structural malformations. We will achieve our objective with these aims:
Aim 1. Identify maternal genes and variants associated with CHD, OFC, and DH;
Aim 2. Identify maternal genes and variants affecting multiple structural malformations;
Aim 3. Identify maternal genes affecting structural malformations through expression levels. The proposed studies are focused on computational and statistical analyses of existing data for test of novel and significant biological hypotheses that have not been fully explored for structural malformations. Hence, our analyses will crucially increase our understanding on the effect of maternal genome on risk of structural birth defects in offspring.
Birth defects occur in approximately 3% of births and the leading cause of death in the first year of life, and a significant cause of morbidity and mortality in all age groups. Our goal is to identify the causes of structural malformations in the context of maternal genome and to translate this knowledge into prevention strategies. This project will crucially increase our understanding on the effect of maternal genome on risk of structural birth defects in offspring.