Comprehensive Characterisation of the RFC1 Repeat in an Australian Cohort

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• RFC1-related disease, including CANVAS, is a late-onset neurodegenerative disorder.
• It is primarily caused by repeat expansions (RE) in the RFC1 gene, specifically AAGGG(n).
• The RFC1 locus is polymorphic with various repeat motifs, complicating diagnosis.

Purpose of the Study:

• To characterize the RFC1 repeat structure.
• To determine the frequency of pathogenic RFC1 alleles in an Australian cohort.
• To investigate RFC1 repeat heterogeneity and its diagnostic implications.

Main Methods:

• Utilized PCR and next-generation sequencing (NGS) techniques.
• Analyzed a cohort of 232 individuals with adult-onset ataxia and 269 healthy controls.
• Employed targeted long-read sequencing for complex allele resolution.

Main Results:

• Biallelic pathogenic RFC1 variants found in 34.1% of affected individuals.
• The majority (93.7%) had AAGGG(n) RE; other pathogenic alleles were also detected.
• Carrier frequency of AAGGG(n) expansion is ~1 in 16 in controls, indicating potential underdiagnosis.

Conclusions:

• RFC1 repeat expansions are a significant cause of late-onset cerebellar ataxia and sensory neuropathy in Australia.
• High carrier frequency suggests pseudodominant inheritance and underdiagnosis.
• RFC1 repeat heterogeneity necessitates improved diagnostic strategies for RFC1-related disease.