RFC1 nonsense and frameshift variants cause CANVAS: clues for an unsolved pathophysiology

Brain. 2022 Nov 21;145(11):3770-3775. doi: 10.1093/brain/awac280.


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. A repeat-primer polymerase chain reaction was used for RFC1 AAGGG intronic expansion identification. RFC1 mRNA expression was assessed by quantitative reverse transcription-polymerase chain reaction. We identified the first two CANVAS affected patients who are compound heterozygous for 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 three 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.

Keywords: RFC1; CANVAS; cerebellar ataxia; repeat expansion; truncating variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bilateral Vestibulopathy* / complications
  • Cerebellar Ataxia* / genetics
  • Humans
  • Peripheral Nervous System Diseases* / complications
  • Peripheral Nervous System Diseases* / genetics
  • RNA, Messenger / genetics
  • Reflex, Abnormal
  • Replication Protein C* / genetics
  • Syndrome


  • RNA, Messenger
  • RFC1 protein, human
  • Replication Protein C