DNA Repair Pathway Variants Are Enriched in Individuals with Biallelic AAGGG CANVAS and RFC1-Related Disease

Cerebellar ataxia, neuropathy and vestibular are flexia syndrome (CANVAS) and RFC1-related disease are most commonly caused by biallelic AAGGG repeat expansions in RFC1. The high population frequency of this expansion compared to the frequency of CANVAS suggests incomplete penetrance. OBJECTIVE: To determine whether polygenic risk factors influence incomplete penetrance in RFC1-related disease.

No actionable clinical change; findings are preliminary genetic research that does not yet alter screening, diagnosis, or management of CANVAS or RFC1-related vestibular areflexia syndrome.

Identifying DNA repair pathway variants as potential modifiers of RFC1/CANVAS disease severity could open new avenues for genetic counselling and future therapeutic targets in vestibular-cochlear degenerative conditions.

1. 01DNA repair pathway gene variants are enriched in individuals with biallelic AAGGG repeat expansions in the RFC1 gene.
2. 02RFC1 repeat expansions are the known cause of CANVAS (cerebellar ataxia, neuropathy, vestibular areflexia syndrome).
3. 03Findings suggest DNA repair mechanisms may influence repeat-expansion instability or disease penetrance.
4. 04Study is observational and does not establish causation between repair variants and clinical severity.
5. 05Results may inform future genetic counselling frameworks for CANVAS patients.

PMID

42473260

DOI

10.1002/mds.70428.

Journal

Movement Disorders

Publication type

research_article

Evidence level

4

Population

Individuals with biallelic AAGGG RFC1 repeat expansions associated with CANVAS or RFC1-related vestibular areflexia syndrome

Intervention

Genetic characterisation of DNA repair pathway variants in RFC1-expansion carriers