Diagnostic Yield and Genetic Burden Analysis of Frequently Mutated Genes in Progressive Ataxia

Hereditary ataxias are a group of disorders characterized by clinical manifestations of cerebellar degeneration. Autosomal dominant and recessive forms have been described, and tandem nucleotide repeat expansion are the most prevalent forms of genetic ataxias. In this study, we aimed to characterize single nucleotide mutations in key genes ( SETX , SACS , ATM , AFG3L2 , TTBK2 , and ELOVL5 ) in 230 patients with progressive ataxias. We identified a total of 180 variants, including 8% loss-of-function (LoF) mutations and 39% nonsynonymous substitutions. Pathogenic or likely pathogenic variations were found in 14 subjects (6%), with mutations most frequently observed in ATM and AFG3L2 . Burden analysis showed an increased burden of LoF variation in patients than in controls, with major contribution from the ATM gene. Our findings emphasize the genetic heterogeneity and requirement of a broader panel for identification of diagnostic variations, and underscore the necessity of functional studies to improve genetic diagnosis in hereditary ataxias.