Complex genetics and disease mechanisms in a Turkish ataxia cohort

Ataxias are a clinically, genetically, and mechanistically heterogeneous group of disorders, characterized by degeneration of the cerebellum. There are significant subtypes of ataxias which also overlap with other neurological disorders, making the precise diagnosis challenging. The developments in next generation sequencing in recent years contributed to the molecular diagnosis of ataxias. It became possible to sequence the coding regions of the genome in a time-saving and cost-effective manner by whole exome sequencing (WES). WES evolved to a powerful tool to identify genetic causes of complex ataxias. In the framework of this thesis, 83 index patients with complex ataxia phenotypes were investigated by WES. Mutations in 18 different genes were identified as the genetic cause in 26 families, which corresponds to a diagnostic yield of 31%. Identification of mutations in hereditary spastic paraplegias and other neurodegenerative disease genes showed that there is a significant overlap among different neurodegenerative disorders. The adaptation of rapidly improving sequencing approaches and detailed clinical information of the remaining patients will help to identify the disease genes in unsolved families. The results presented here complement the picture of the molecular basis of ataxias in Turkey. This will hopefully pave the ways for more precise diagnosis in future and will also contribute to the development of therapeutic approaches in ataxias.