Lightning Talk and Poster Presentation GENEMAPPERS 2024

Genetic discovery and diagnosis of ataxia in an Australian cerebellar ataxia cohort (#12)

Haloom Rafehi 1 2 , Justin Read 3 4 , Liam G Fearnley 1 2 , David J Szmulewicz 5 6 , Kayli C Davies 3 , Penny Snell 3 , Genevieve Thompson 3 , Liam Scott 1 2 , Mark F Bennett 1 2 7 , Martin Delatycki 3 4 8 , Melanie Bahlo 1 2 , Paul Lockhart 3 4
  1. Population Health and Immunity, WEHI, Parkville, Victoria, Australia
  2. Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
  3. Bruce Lefroy Centre, Murdoch Children’s Research Institute, Parkville, Victoria, Australia
  4. Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia
  5. Cerebellar Ataxia Clinic, Eye and Ear Hospital, Melbourne, Victoria, Australia
  6. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia
  7. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, Australia
  8. Victorian Clinical Genetics Services, Parkville, Victoria, Australia

Background: cerebellar ataxias (CA) are a group of hereditary neurodegenerative conditions that are often caused by repeat expansions (RE) of short tandem repeats (STR) and have historically been difficult to diagnose. Standard diagnosis in Australia relies on limited diagnostic assays which test for six of sixteen known ataxia REs. As a result, only ~10% of individuals with a clinical diagnosis receive a genomic diagnosis. Recent methodological advances have made detection with whole genome sequencing (WGS) and long read sequencing such as Oxford Nanopore Technology (ONT) feasible, including both the detection and sizing of pre-defined REs and the discovery of novel REs.

Aim: to determine if we can improve the diagnostic rate CA using WGS and ONT.

Method: we recruited 115 Australian individuals with CA with negative diagnostic SCA RE panel testing. Using WGS and ONT we screened known ataxia loci and investigated novel genetic causes of ataxia.

Results: analysis of the WGS data identified a novel GAA expansion in FGF14 that causes an autosomal-dominant adult-onset ataxia (SCA27B). This RE accounted for 22% (25/115) of the cohort, with mounting evidence indicating SCA27B is one of the most common causes of adult-onset ataxia world-wide. Further analysis for novel REs in the cohort is on-going. In addition, we identified individuals with known pathogenic RE causing CANVAS (n=5), SCA8 (2), SCA36 (1) and Friedreich’s ataxia (1). An additional seven cases with ataxias caused by SNPs were also identified, giving a 28% solve rate. Conclusion: our work to date has substantially improved genetic diagnostics rates in an ataxia cohort, however our work highlights that challenges remain despite substantial gains in diagnostic rates. In addition, the outcome of this project will be the benchmarking of WGS and ONT as a diagnostic tool for RE disorders such as ataxia.