Comprehensive Characterisation of the RFC1 Repeat in an Australian Cohort

Davies, KC; Rafehi, H; Fearnley, LG; Snell, P; Gillies, G; Field, TA; Halm&#225;gyi, GM; Kumar, KR; Pope, K; Smyth, R; Tomlinson, SE; Tisch, S; Tang, CC; Watson, SRD; Wellings, T; Wu, KHC; Szmulewicz, DJ; Delatycki, MB; Bahlo, M; Lockhart, PJ

Author(s): Davies, KC; Rafehi, H; Fearnley, LG; Snell, P; Gillies, G; Field, TA; Halmágyi, GM; Kumar, KR; Pope, K; Smyth, R; Tomlinson, SE; Tisch, S; Tang, CC; Watson, SRD; Wellings, T; Wu, KHC; Szmulewicz, DJ; Delatycki, MB; Bahlo, M; Lockhart, PJ;
Details: Publication Year 2025-06-07,Volume 24,Issue #4,Page 111
Journal Title: Cerebellum
Abstract: 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.
Publisher: Springer
Keywords: Humans; *Replication Protein C/genetics; Australia/epidemiology; Male; Female; Middle Aged; Cohort Studies; *DNA Repeat Expansion/genetics; Adult; Aged; Gene Frequency; *Cerebellar Ataxia/genetics; Alleles; Canvas; Cerebellar ataxia; Rfc1; Repeat expansion; Repeat heterogeneity
Research Division(s): Genetics and Gene Regulation
PubMed ID: 40481300
Publisher's Version: https://doi.org/10.1007/s12311-025-01867-2
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-06-26 09:55:15

Last Modified: 2025-06-26 09:56:13