Abstract
Introduction Numerous ataxia genes have been discovered in recent years, including repeat expansions in RFC1, FGF14, THAP11 and ZFHX3. However, genetic testing approaches available in current clinical practice may miss these variants, meaning individuals remain undiagnosed.
Background/Objectives This project applies long read-sequencing (LRS) to individuals with unsolved spastic-ataxias, aiming to resolve further cases and narrow the diagnostic gap.
Methods 34 individuals with spastic-ataxia were recruited from the Concord Hospital Neuromuscular Clinic and phenotypic data obtained. Targeted LRS using the Oxford Nanopore Technologies platform has been undertaken in 24 samples to date, using Read Until adaptive sampling of a custom panel of ~470 genes associated with spastic-ataxias or mimics. An interim analysis was undertaken in 17 samples to evaluate for short-tandem repeat expansions.
Results An FGF14 repeat expansion (SCA27B) was identified in four individuals (4/17, 24%), and a biallelic RFC1 repeat expansion (CANVAS) in one individual, with a total diagnostic rate for newly discovered repeat expansions of 29% (5/17). Results are yet to be analysed for single nucleotide variants, insertions and deletions, which may identify further causes.
Conclusion Our study suggests SCA27B is a relatively common cause amongst unsolved spastic-ataxias in Australia. Given treatment is available, with most patients responding to 4-aminopyridine, this emphasises the need for clinically-available testing to allow diagnostic confirmation.
LRS is a promising technology for genetically evaluating spastic-ataxias, as many genes and genetic variant types can be assessed in a single test, including recently discovered repeat expansions that are missed on current standard genetic testing.
