Investigation of the non-immune hydrops fetalis-related signaling pathwayusing in silico methods

Non-Immune Hydrops Fetalis (NIHF) is a fatal pathology characterized by the presence of at least two of the following findings; subcutaneous edema, pleural effusion, pericardial effusion or ascites, in a fetus for reasons besides maternal alloimmunization. The incidence and mortality rates of NIHF are 1/1700-3000 and 50-98%, respectively. It is known that monogenic mutations account for approximately 85% of the etiology of NIHF, but the exact list of NIHF-related genes and mutations is not known. In addition, the molecular etiopathogenesis of NIHF, the molecules and biological processes that play a central role in NIHF formation and potential subgroups of NIHF have not been identified. Additionally, there is no molecularly-targeted treatment method specific to NIHF, and when NIHF is diagnosed medical termination of the pregnancy is recommended all over the world. The aim of this thesis study is to review the monogenic genetic etiology of NIHF and to determine the NIHF-associated cellular signaling pathway using this gene list and various in silico analysis methods. In this context, it was determined that a total of 415 single gene variations in 175 different genes are associated with the formation of NIHF. The functional enrichment analysis (FEA) performed with this gene list indicated that Ras/MAPK signaling pathway, muscle contraction, and lysosome proteins are present in the top three biological processes that play a role in NIHF. After that, the protein-protein interactions (PPE) network consisting of 113 proteins and 229 junctions made by the NIHF proteins and the hub proteins of the network were determined. Finally, NIHF-associated cell signaling pathway was established by considering the data obtained via FEA and PPE, from pathway databases and literature. The NIHF signaling pathway showed that the NIHF could be divided into six subgroups, and the first three subgroups, according to organization and number of members, were "FLT4/Ras/MAPK Signaling Pathway", "Ca+2 Signaling Pathway", and "Bioenergetics and Metabolism". In conclusion, with this thesis, the list of genes and mutations that make up the monogenic genetic etiology of NIHF was compiled and by using this list and in silico analysis methods the map of the NIHF-related cell signal pathway and the potential subgroups of NIHF were determined.