Objective: To present a case with CANVAS with a novel repeat motif.

Background: CANVAS is a late-onset neurological syndrome of combined vestibular, neuropathic, and cerebellar dysfunction. Biallelic, intronic pentanucleotide repeat expansions in the replication factor C subunit (RFC1) gene are a frequent cause of CANVAS. Pathogenic alleles differ in both sequence (often AAGGG but also AAAGG, and ACAGG) and size (usually >400) from the reference sequence (AAAAG)₁₁.

Method: We performed a comprehensive clinical examination of a 77-year-old man with CANVAS suspicion. We tested for the RFC1 repeat expansion using a duplex PCR, Sanger sequencing, and repeat-primed PCR (RP-PCR).

Results: The patient experienced diplopia upon head-turning at 73 years, accompanied by progressive balance problems and dizziness. Upon examination, he presented with a full-blown picture of CANVAS including bilateral vestibulopathy (quantitative head impulse testing), cerebellar ataxia including gaze directional nystagmus and dysmetria, and sensory neuropathy (reduced sensor nerve action potentials in the ulnar and sural nerve). Notably, he had no history of dry cough. A cranial MRI revealed global brain atrophy including the cerebellum.
Duplex PCR revealed a moderately expanded product. Accordingly, Sanger sequencing of the repeat-flanking PCR product showed a total of 43 pentanucleotide repeats, containing 17 ACGGG repeats, 11 AAGGG repeats, and 1-7 motifs of AAAGG, ACGGA, AACGG, and AAGGA in mixed order. RP-PCR confirmed the presence and number of ACGGG and AAGGG repeats, and absence of the wild type motif.
Subsequently, RP-PCR for ACGGG was used to screen another 57 suspected CANVAS patients with variable repeat sizes in RFC1 (as determined by duplex PCR), yielding no additional carriers.

Conclusion: For the first time, we describe a patient presenting with complete CANVAS who carries a rather small extended, biallelic RFC1 repeat including an ACGGG motif. Our results suggest that this repeat configuration might be a rare cause of the syndrome. Future studies are warranted to clarify whether the absence of dry cough is associated with this newly described repeat.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-rfc1-repeat-motif-acggg-in-a-patient-with-cerebellar-ataxia-neuropathy-and-vestibular-areflexia-syndrome-canvas/