Searching for genetically determined new causes of severe/lethal multiple syndromes in human fetuses

The main objectives of the project are: 1. expanding the current knowledge on genetic causes of severe and lethal human developmental defects; 2. identification of new genetic factors in their etiology with the use of genomic research technologies including CGH microarray (aCGH) testing and full exome sequencing (WES) from the material collected from the fetus in the second and third trimesters; 3. assessment of the frequency of pathogenic variants including submicroscopic chromosomal rearrangements and single nucleotide variants in a group of fetuses with at least two malformations, with severe phenotype and poor prognosis, often lethal; 4. analysis of the correlation of aCGH results with the results of WES sequencing in order to identify aneuploidy and large chromosomal aberrations. The practical goals of the project include: 1. development of an algorithm for diagnostic management in fetuses with multiple developmental defects using the aCGH and WES techniques. 2. development of rules for the interpretation of WES test results and assessment of their importance for genetic counseling in families at risk in relation to multiple congenital abnormalities. 3. development of methods allowing for comprehensive diagnosis of numerical and large structural chromosomal aberrations (aneuploidy, large deletions / amplification) and point mutations using a uniform technology based on next-generation sequencing.

The authors of the project have undertaken research into this thematic scope in order to explain the previously unknown causes and mechanisms of severe and lethal developmental defects. This will allow a better understanding of the biology of human development and the creation of new diagnostic tests aimed at determining the risk of their occurrence, which will also affect the development of family counseling. The application of genomic methods to this group of diseases should lead to the discovery of new pathogenetic conditions. The importance of these findings may extend beyond the problem of malformations, as it can be expected that some of the genes associated with abnormal pregnancy development may also be important in the pathogenesis of other non-lethal human diseases. The planned research will be carried out for the first time in Poland and as one of the first in the world, and their results will have both cognitive and practical significance.