Genetic Studies in Gestational Trophoblastic Disease

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DESCRIPTION (provided by applicant): A complete hydatidiform mole (CHM) is an abnormal pregnancy with hyperproliferative trophoblast and no fetus. Genetically, most CHM are diploid androgenetic (AnCHM), containing only paternal DNA. This results in uniparental paternal disomy of all chromosomes and AnCHM can therefore be considered a genome-wide imprinting disorder with unbalanced expression of imprinted genes, which results in abnormal trophoblast development. Interestingly, rare familial and non-familial recurrent hydatidiform moles have normal biparental inheritance (BiCHM), but have genome-wide defects of imprinting marks that are established in the female gamete. Affected women in these families have an autosomal recessive mutation linked in most cases to 19q13.4. The hypothesis for this project is that CHM as a disorder creates an ideal resource to study genomic imprinting in reproductive health and disease. By combining studies on BiCHM and AnCHM, we have an opportunity to identify in parallel a gene that affects establishment of imprinting marks as well as its targets. In specific aims 1 and 2 we propose to study DNA from affected women with familial and non-familial recurrent CHM to identify the gene that, when mutated, causes the development of BiCHM with genome-wide imprinting abnormalities. Identifying this gene will significantly contribute to the understanding of how maternal imprinting marks are established in the female gamete or maintained in the early embryo. In specific aims 3 and 4 we will perform DNA methylation screens to find imprinted genes in AnCHM. This will lead to the discovery of novel genes that are imprinted in trophoblast. A subset of which will be those targets of the BiCHM gene that are responsible for the CHM phenotype. Together these studies will benefit our understanding of the pathogenesis of CHM and the role of imprinted genes in placental function and fetal development.