Abstract
Abstract Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an inherited late-onset neurological disease caused by bi-allelic AAGGG pentanucleotide expansions within intron 2 of RFC1. Despite extensive studies, the pathophysiological mechanism of these intronic expansions remains elusive. We screened by clinical exome sequencing two unrelated patients presenting with late onset ataxia. Repeat Primer-PCR was used for RFC1 AAGGG intronic expansion identification. RFC1 mRNA expression was assessed by quantitative reverse transcription PCR We identified the first two CANVAS affected patient who are compound heterozygous for a RFC1 truncating variants (p.Arg388* and c.575delA, respectively) and a pathological AAGGG expansion. RFC1 expression studies in whole blood showed a significant reduction of RFC1 mRNA for both patients compared to 3 patients with bi-allelic RFC1 expansions. In conclusion, this observation provides clues that suggest bi-allelic RFC1 conditional loss of function as the cause of the disease.