THE ROLE OF NEXT-GENERATION SEQUENCING IN THE DISCOVERY OF NOVEL GENETIC CAUSES OF DYSTONIA

Aim: The scope of this thesis is to identify through a Next-Generation Sequencing (NGS) approach novel genes and genetic variants associated with hereditary dystonia. Background: Dystonia is a hyperkinetic movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures. The recent advances in molecular genetics (i.e., NGS technologies) are leading to the discovery of an increasing number of genetic dystonia forms. There is great interest in the study of the etiology of dystonia since the discovery of underlying biological mechanisms may facilitate the development of specific targeted therapies and contribute to a better knowledge of the disease mechanisms of non-genetic forms of dystonia as well. Results: Here we present: 1) a new genetic form of dystonia associated with a novel disease-causing gene (VPS11); 2) the expansion of the phenotypic spectrum associated with known causative genes (VPS16, VPS13A, and KMT2B); 3) a novel group of hereditary dystonias sharing common disease mechanisms (i.e., HOPS-associated Neurological Disorders - HOPSANDs); 4) novel pathogenic variants in already known isolated, combined and complex dystonia genes (VPS16, VPS13A, VPS13C, NUS1, KMT2B). Conclusions: The NGS approach in the field of dystonia increases the chance of early diagnosis, supports neurogeneticists in performing well-informed genetic counselling, helps the neurologist in clinical management, improves the understanding of biological disease mechanisms, and allows for the identification of specific candidate therapeutic targets for each genetic form.