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<p><i>RFC1</i>-related disease, which includes cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), is a late-onset neurodegenerative disorder primarily caused by biallelic AAGGG<sub>(n)</sub> repeat expansions (RE) in <i>RFC1</i>. The <i>RFC1</i> locus is highly polymorphic, with multiple pathogenic and non-pathogenic repeat motifs identified. This study aimed to characterise the structure of the <i>RFC1</i> repeat and determine the pathogenic allele frequency in an Australian cohort. Using a combination of PCR and next generation sequencing techniques, we provide a comprehensive characterisation of the <i>RFC1</i> repeat locus in an Australian cohort of 232 individuals with adult-onset ataxia and 269 healthy controls. Biallelic pathogenic <i>RFC1</i> variants were identified in 34.1% of affected individuals. The overwhelming majority (93.7%) have biallelic AAGGG<sub>(n)</sub> RE, although other pathogenic alleles, including ACAGG<sub>(n)</sub>, AAAGG<sub>(&gt;500)</sub> and the Māori AAAGG<sub>(10−25)</sub>AAGGG<sub>(n)</sub>AAAGG<sub>(4−6)</sub> configuration were detected in some affected individuals. We also demonstrate the utility of targeted long-read sequencing in resolving complex alleles. The carrier frequency of the pathogenic AAGGG<sub>(n)</sub> expansion was approximately 1 in 16 in controls, highlighting the potential for pseudodominant inheritance and the likelihood that <i>RFC1</i>-related disease is underdiagnosed. We further demonstrate the significant <i>RFC1</i> repeat heterogeneity, identifying 16 distinct motifs, complex repeat structures, and at least six motifs with an allele frequency &gt; 1%. The frequency of <i>RFC1</i>-related disease in individuals with adult-onset cerebellar ataxia and the high carrier frequency of pathogenic <i>RFC1</i> alleles in the Australian population underscores the need for improved diagnostic strategies. Our findings indicate <i>RFC1</i> RE are a major cause of late-onset cerebellar ataxia and sensory neuropathy in Australia and provide further insights into <i>RFC1</i> repeat diversity.</p>

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Comprehensive Characterisation of the RFC1 Repeat in an Australian Cohort

  • 期刊论文

  • 发表日期：

    2025年6月7日

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  • Kayli C. Davies,
  • Haloom Rafehi,
  • Liam G. Fearnley,
  • Penny Snell,
  • Greta Gillies,
  • Tess A. Field,
  • Gábor M. Halmágyi,
  • Kishore R. Kumar,
  • Kate Pope,
  • Renee Smyth,
  • Susan E. Tomlinson,
  • Stephen Tisch,
  • Chi-Chang Tang,
  • Shaun R. D. Watson,
  • Thomas Wellings,
  • Kathy H. C. Wu,
  • David J. Szmulewicz,
  • Martin B. Delatycki,
  • Melanie Bahlo,
  • Paul J. Lockhart

摘要

RFC1-related disease, which includes cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), is a late-onset neurodegenerative disorder primarily caused by biallelic AAGGG(n) repeat expansions (RE) in RFC1. The RFC1 locus is highly polymorphic, with multiple pathogenic and non-pathogenic repeat motifs identified. This study aimed to characterise the structure of the RFC1 repeat and determine the pathogenic allele frequency in an Australian cohort. Using a combination of PCR and next generation sequencing techniques, we provide a comprehensive characterisation of the RFC1 repeat locus in an Australian cohort of 232 individuals with adult-onset ataxia and 269 healthy controls. Biallelic pathogenic RFC1 variants were identified in 34.1% of affected individuals. The overwhelming majority (93.7%) have biallelic AAGGG(n) RE, although other pathogenic alleles, including ACAGG(n), AAAGG(>500) and the Māori AAAGG(10−25)AAGGG(n)AAAGG(4−6) configuration were detected in some affected individuals. We also demonstrate the utility of targeted long-read sequencing in resolving complex alleles. The carrier frequency of the pathogenic AAGGG(n) expansion was approximately 1 in 16 in controls, highlighting the potential for pseudodominant inheritance and the likelihood that RFC1-related disease is underdiagnosed. We further demonstrate the significant RFC1 repeat heterogeneity, identifying 16 distinct motifs, complex repeat structures, and at least six motifs with an allele frequency > 1%. The frequency of RFC1-related disease in individuals with adult-onset cerebellar ataxia and the high carrier frequency of pathogenic RFC1 alleles in the Australian population underscores the need for improved diagnostic strategies. Our findings indicate RFC1 RE are a major cause of late-onset cerebellar ataxia and sensory neuropathy in Australia and provide further insights into RFC1 repeat diversity.