A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families

Brain. 2020 Oct 1;143(10):2904-2910. doi: 10.1093/brain/awaa263.

Abstract

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel RFC1 repeat expansion motif, (ACAGG)exp, in three affected individuals. This motif was associated with additional clinical features including fasciculations and elevated serum creatine kinase. These features have not previously been described in individuals with genetically-confirmed CANVAS. Haplotype analysis showed our patients shared the same core haplotype as previously published, supporting the possibility of a single origin of the RFC1 disease allele. We analysed data from >26 000 genetically diverse individuals in gnomAD to show enrichment of (ACAGG) in non-European populations.

Keywords: neuropathy; sensory neuropathy; cerebellar ataxia; vestibular areflexia syndrome; CANVAS; RFC1; repeat expansion.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Asians / genetics*
  • Bilateral Vestibulopathy / complications
  • Bilateral Vestibulopathy / diagnosis
  • Bilateral Vestibulopathy / genetics*
  • Cerebellar Ataxia / complications
  • Cerebellar Ataxia / diagnosis
  • Cerebellar Ataxia / genetics*
  • Cohort Studies
  • DNA Repeat Expansion / genetics*
  • Female
  • Humans
  • Indonesia
  • Male
  • Middle Aged
  • Pedigree
  • Replication Protein C / genetics*

Substances

  • RFC1 protein, human
  • Replication Protein C