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Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is an adult-onset autosomal recessive neurodegenerative disorder caused by biallelic pentanucleotide intronic expansions in RFC1 and, more recently, by compound heterozygosity with loss-of-function sequence variants (PMID:35306791). CANVAS manifests with progressive cerebellar ataxia (HP:0001251), cerebellar atrophy (HP:0001272), sensory neuronopathy, and bilateral vestibular areflexia.
In a cohort of 15 CANVAS patients carrying a single (AAGGG)n expansion, whole-genome or exome sequencing identified seven affected individuals from five unrelated families harboring a second truncating RFC1 variant in trans (e.g., c.1267C>T (p.Arg423Ter), c.1739_1740del (p.Lys580SerfsTer9), c.2191del (p.Gly731GlufsTer6), c.2876del (p.Pro959GlnfsTer24)) with confirmed segregation (PMID:36289003).
A representative novel variant, c.1147C>T (p.Arg383Ter), was identified in trans with a pathogenic intronic expansion in an adult proband; long-read sequencing confirmed allelic phase and patient RNA studies demonstrated complete absence of transcript from the nonsense allele, consistent with nonsense-mediated decay (PMID:36524104).
Genetic evidence: autosomal recessive inheritance with compound heterozygous expansions and LoF variants in at least eight unrelated probands across six families supports a Strong gene–disease association.
Functional assays in patient-derived cells for c.1147C>T, c.1267C>T, and c.2876del variants demonstrated reduced RFC1 transcript and protein levels, confirming loss-of-function as the pathogenic mechanism (PMID:36289003; PMID:36524104).
No studies have refuted this association. Additional reports of biallelic RFC1 mutations in patients with immune-mediated neuropathies indicate an expanded phenotypic spectrum (PMID:37853169).
Key Take-home: RFC1 should be included in genetic testing panels for adult-onset cerebellar ataxia and sensory neuropathy to detect both intronic expansions and coding loss-of-function variants.
Gene–Disease AssociationStrongEight unrelated probands with biallelic pathogenic RFC1 variants from six families, segregation in five families, concordant functional data Genetic EvidenceStrongCompound heterozygous intronic expansions and loss-of-function variants identified in eight probands; reached genetic evidence cap Functional EvidenceModeratePatient cell assays show nonsense-mediated decay and reduced transcript/protein for multiple truncating variants consistent with loss-of-function |