The molecular architecture of ataxias in Turkey

Ataxias are a clinically, genetically, and mechanistically heterogeneous group of neurological disorders characterized by motor incoordination, resulting from dysfunction of the cerebellum and its connections. Ataxias with different phenotypes overlap and make a precise clinical diagnosis challenging. In recent years, advances in next generation sequencing (NGS) have drastically contributed to the molecular diagnosis of ataxias. With whole exome sequencing (WES), one of the NGS technologies, it has become possible to analyse the coding regions of the genome in a time-saving and cost effective manner. WES, which is a state-of-the-art method, has evolved into an efficient tool for identifying genetic causes of complex ataxias. In the framework of this thesis, 95 index patients with complex ataxia phenotypes were investigated by WES. Causative mutations in 28 different genes were identified in 40 families, this corresponds to a diagnostic yield of 42%. A significant overlap among different neurodegenerative disorders has been demonstrated by identifying mutations in hereditary spastic paraplegias and other neurodegenerative disease genes. Rapidly improving sequencing technologies, collaborative projects, and detailed clinical information will help to identify disease genes in remaining unsolved families. The results presented in this thesis will hopefully contribute to pave the ways for more definitive diagnosis of ataxias in the future and to developing molecular therapies.