Late-onset ataxia is a reason of frequent neurological consultation, but its cause often remains unknown. Cerebellar dysfunction, proprioceptive loss or vestibular impairment can cause ataxia, when in combination, also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Both sporadic and familial cases of CANVAS have been reported, which led us to hypothesise a recessive transmission. By applying non-parametric linkage analysis and whole-genome sequencing, we have identified an intronic pentanucleotide repeat expansion in RFC1 as the cause of CANVAS and a common cause of late-onset sensory ataxia. The biallelic repeat expansion showed complete segregation in 23 cases from 11 families. Thirty-three (22%) out of 150 sporadic cases with late-onset ataxia tested also carried the biallelic repeat expansion and frequency was higher in patients with sensory neuronopathy and cerebellar involvement or full-blown CANVAS disease. The expansion is located in the polyA tail of an Alu element and differs in terms of both size and nucleotide sequence from the reference allele. The high frequency of the repeat expansion tested cases, together with an allelic carrier frequency of 0.7% of Europeans, indicate that it represents a frequent cause of late-onset ataxia, with clinical similarities and disease frequency to Friedreich’s ataxia.
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