Özet:
Ataxias are a diverse group of genetically, clinically and mechanistically heterogeneous neurodegenerative disorders. There is significant overlap in the phenotype of different subtypes of ataxia, which can also manifest as additional symptoms with other neurological diseases; thus making a precise clinical diagnosis becomes challenging. After the elimination of common late-onset spinocerebellar ataxias, still a high number of ataxia patients remain genetically undiagnosed. In recent years, next generation sequencing (NGS) technologies have proven to be very powerful to detect the genetic causes of both monogenic and complex disorders. Among these, whole exome sequencing is especially effective in the identification of disease genes, particularly in pedigrees manifesting a Mendelian inheritance pattern. In this study, 47 pedigrees were investigated by whole exome sequencing to dissect the cause of disease. This pipeline was coupled with homozygosity mapping in recessive cases to detect homozygous strecthes likely to contain mutated disease genes. In the framework of this thesis, we identified and validated the genetic causes of ataxia in almost half (43%) of the pedigrees investigated. This diagnostic yield, in accordance with the literature, is a demonstration of the usefulness of the approach in definitive diagnosis. Detailed phenotyping of the remaining individuals in our pedigrees, combined with the adaptation of rapidly evolving approaches to analyze the data, are expected to pave the ways to identification of novel disease genes in the yet unsolved families.
