INVESTIGATION OF MOLECULAR GENETIC DIAGNOSIS USING WHOLE EXOME SEQUENCING IN PATIENTS WITH CONGENITAL ANEMIA AND DISCOVERY OF NOVEL RESPONSIBLE GENES
Project no. 21906 · Status: Kapanmış (Yayın bekleniyor) · 2020
Summary
Background: Congenital hemolytic anemias are a group of genetic heterogeneous diseases that result from mutations in genes encoding proteins involved in erythrocyte production or structure. It is not always possible to determine the specific diagnosis evaluating clinical findings and conventional laboratory tests. With the acceleration of developments in the field of molecular genetics, the success of diagnosis in hereditary hemolytic anemia is gradually increasing. However, molecular diagnosis cannot be made in 20-40% of patients with the targeted new generation sequencing analysis panels that are still in use. In order to reveal the genes responsible for rare types, more comprehensive molecular studies are required. The aim of this study was to discover novel candidate genes responsible for rare hereditary hemolytic anemias, to reveal new molecular targets that may be candidates for treatment, and to expand the genotype-phenotype relationship. Methods: Six congenital hemolytic anemia families either having more than one affected cases in the family and/or consanguineous parents of an affected individual were enrolled in the project. Prior to this project, the families had been evaluated using a next generation sequencing panel, and no molecular diagnosis could be established. Whole exome sequencing was performed in nine cases from six families to investigate novel genes and/or variants. Results: As a result of whole exome sequencing analysis, mutations in genes known to be responsible for congenital hemolytic anemia (HBA2 and PKLR) were identified in five families. In Case 13, the molecular etiology could not be identified. Conclusion: As a result of this study, it is considered that the PKLR c.1516G>A variant (rs8177988), which was previously recorded as benign in the ClinVar database, is pathogenic. Whole exome sequencing provided preliminary data for further functional studies In this project, the molecular etiopathogenesis of rare congenital anemia was investigated by analyzing the cases whose molecular etiology could not be determined by whole exome sequencing, which were evaluated with a large next generation sequencing analysis panel containing the genes responsible for hereditary hemolytic anemia. Nine cases from six families were included in the study. As a result of whole exome sequencing analysis, mutations in genes (HBA2, PKLR) known to be responsible for congenital hemolytic anemia were detected in four families. A candidate gene thought to be responsible for hereditary hemotic anemia has been identified in one family.