Sharhorodska Y. The role of maternal factors and polymorphic variants of one-carbon metabolism genes (MTHFR, MTHFD1) and vascular endothelial growth factor (VEGF) in determining the risk of fetal congenital heart defect

The thesis paper presents a theoretical underpinning and a new solution to the applied research task of determining the informative value of genetic testing of allelic variants of the MTHFR, MTHFD1, VEGF genes and the level of vascular endothelial growth factor across pregnancy for use in the system of periconception preventive measures, prediction and early detection of congenital heart defect of the fetus. Possible risk factors, character of reproductive anamnesis, course and termination of pregnancy in women with congenital heart defect in descendants were elucidated, and recommendations were elaborated to improve of the effectiveness of prenatal diagnosis and genetic counselling of this patient cohort. It has been shown for the first time that in pregnant women with congenital defects of heart and/or its large vessels in the fetus, the level of vascular endothelial growth factor is higher in the period of 20-30 weeks of gestation, compared to pregnant women without congenital malformations in the fetus, this contributing to consider it a biochemical marker of CHD in the fetus. There has been obtained allelic and genotypic distribution by loci MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131) and MTHFD1 1958G>A (rs2236225), locus 405C>G (rs2010963) of the gene of VEGF among women with congenital heart defects in the fetus. It has been proven that the presence of a MTHFR 677T allele and VEGF 405GG genotype in a woman is a genetic factor for the increased risk of emergence of congenital heart defects in children. It has been found that the mother's age was not a factor in the increased risk of having a baby with CHD. There has been described for the first time the mutation c.493G>T (p.Glu165*) of the ZEB2 gene and its phenotypic correlation with heart defect in the rare Mowat-Wilson syndrome. The identified significant differences in the structure of congenital heart defects diagnosed in the prenatal and postnatal periods revealed a reserve for improving prenatal diagnosis of congenital heart defects, which discloses only 40.1% of cases. It has been shown that pregnant women with congenital defect of heart and/or its large vessels in the fetus are at risk for obstetric and perinatal complications, and children with CHD are more likely to be born premature, which requires additional measures from the obstetric service in case of prenatal diagnosis of CHD in the fetus. An algorithm for genetic counseling of women with CHD in the fetus in prenatal, postnatal and subsequent periconception periods has been proposed for implementation.