A novel intronic GAA repeat expansion in FGF14 causes autosomal dominant adult-onset ataxia (SCA50, ATX-FGF14)

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified a novel intronic GAA repeat expansion in the gene encoding Fibroblast Growth Factor 14 ( FGF14 ). Genetic analysis identified 4/95 previously unresolved Australian affected individuals (4.2%) with (GAA)>335 and a further nine individuals with (GAA)>250. Notably, PCR and long-read sequence analysis revealed these were pure GAA repeats. In comparison, no controls had (GAA)>300 and only 2/311 control individuals (0.6%) encoded a pure (GAA)>250. In a German validation cohort 9/104 (8.7%) of affected individuals had (GAA)>335 and a further six had (GAA)>250. In comparison no controls had (GAA)>335 and 10/190 (5.3%) encoded (GAA)>250. The combined data suggests (GAA)>335 are disease-causing and fully penetrant [P-value 6.0×10−8, OR 72 (95% CI=4.3-1227)], while (GAA)>250 is likely pathogenic, albeit with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with a clinical phenotype that may include vestibular impairment, hyper-reflexia and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2=0.44 p=0.00045, slope = -0.12). This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansion loci via model free, genome-wide analysis and identifies SCA50/ATX-FGF14 is a frequent cause of adult-onset ataxia. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to PJL MBD and HR. HR was supported by a NHMRC Emerging Leadership 1 grant (1194364) and MB was supported by an NHMRC Leadership 1 grant (1195236). Additional funding was provided by the Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Program and the Murdoch Childrens Research Institute. NB and KL are supported by research grants from the Deutsche Forschungsgemeinschaft (DFG FOR 2488). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Royal Childrens Hospital Human Research Ethics Committee approved this work (HREC 28097). The Walter and Eliza Hall Institute of Medical Research Ethics Committee approved this work (HREC 18/06). The Ethics committee of the University of Lubeck approved this work (AZ16-039). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are either contained in the manuscript or available upon reasonable request excluding material unable to be shared for ethics/confidentiality purposes