GR.2 A deep intronic FGF14 GAA repeat expansion causes late-onset cerebellar ataxia

Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome and long-read search for expansions in patients with LOCA. enrolled 66 French-Canadian, 228 German, 20 Australian 31 Indian patients. Pathogenic mechanisms were studied post-mortem cerebellum induced pluripotent stem cell (iPSC)-derived motor neurons from 2 Results: identified 128 who carried an autosomal dominant GAA expansion the first intron FGF14 gene. was present 61%, 18%, 15% 10% cohorts, respectively. pathogenic threshold determined be (GAA) ≥250 , although incomplete penetrance observed 250-300 range. Patients developed a slowly progressive syndrome at average age 59 years. Patient-derived both showed reduction RNA protein expression compared controls. Conclusions: This intronic, dominantly inherited represents one most common genetic causes LOCA uncovered date.