Investigation of genetic etiology in families with multiple affected cases with similar clinical findings by the whole exome sequencing method

Genetic diseases are examined under two large groups as Mendelian and non-Mendelian diseases. Approximately 80% of rare diseases are thought to be of genetic origin, and many of them are reported to be compatible with the monogenic Mendelian inheritance model. If clinical findings lead to a syndrome with known genetic etiology, targeted genetic tests can be applied in these cases to contribute to the diagnosis or confirm the diagnosis. In cases where a diagnostic approach cannot be established with clinical findings, classical genetic tests are applied, but despite all these applications, approximately half of the cases can be diagnosed. In such cases, new generation sequencing technologies are used that provide access to diagnosis from the test described as "reverse diagnosis". The most commonly used type of these technologies is whole-exome sequencing (WES). In this thesis, 3 index cases and 5 individuals from three families with at least two affected cases with similar clinical findings, incompatible clinical findings with a known syndrome, and no microscopic and submicroscopic changes were investigated. Changes that may play a role in the etiology in these individuals were investigated using the WES method. As a result of the analyzes performed, variants in four different genes (CCDC88C, FLNA, RP1L1, NUP188) possibly related to clinical findings were detected in index cases. Two of these variants, which were confirmed by Sanger sequencing and family studies were conducted, were new changes whose association was not previously reported (FLNA c.1829-1G>T (p.(?)) and NUP188 c.124C>T (p.Arg42Ter), two of them were previously reported variants (CCDC88C c.1915C>T (p.Arg639Ter) and RP1L1 c.455G>A (p.Arg152Gln). Although a change was detected in all cases included in the study, it would be too optimistic to claim that the WES technique will provide a similar diagnostic contribution in each case due to the small number of patients and selection criteria. Our study shows the contribution of WES to identifying new variations and searching for new disease-related genes as well as in known disease-related genes.