DNA Repair Pathway Variants Are Enriched in Individuals with Biallelic AAGGG CANVAS and RFC1-Related Disease
- Author(s)
- Wang, X; Fearnley, LG; Davies, KC; Snell, P; Lee, S; Jackson, VE; Read, J; Milton, M; Harding, IH; Delatycki, MB; Szmulewicz, DJ; Lockhart, PJ; Bahlo, M; Rafehi, H;
- Journal Title
- Movement DIsorders
- Publication Type
- Jul 19
- Abstract
- BACKGROUND: 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. METHODS: Biallelic RFC1 AAGGG status was profiled in Genomics England (GEL) and the UK Biobank (UKB) discovery cohorts and a replication Australian ataxia cohort (AAC). Polygenic score (PGS) analysis was performed with variants identified in a Huntington's Disease age at onset study. RESULTS: We identified 56 (GEL) and 18 (UKB) biallelic individuals with ataxia and/or neuropathy, and 26 (GEL) and 207 (UKB) age-matched biallelic carriers with no report of ataxia or neuropathy. Meta-analysis of GEL and UKB identified elevated PGS in biallelic affected individuals (OR = 1.43, p = 2.2 × 10(-3)) compared to controls, but not in the biallelic carriers (OR = 1.01, P = 0.92). The variant rs245100, upstream MSH3, was the biggest contributor to this elevated risk (OR = 2.35, adjusted p = 0.02). Replication in the AAC showed elevated PGS in individuals with molecular confirmation of CANVAS or RFC1-related disease (n = 54) (OR = 1.93, P = 4.4 × 10(-5)), and enrichment of rs245100 (OR = 4.24, p = 1.0 × 10(-4)). CONCLUSION: These results indicate that modifier variant burden alters disease penetrance and presentation in RFC1-related disease and determines an increased incidence of ataxia and neuropathy in biallelic individuals. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
- Publisher
- Wiley
- Keywords
- DNA mismatch repair; cerebellar ataxia; genetics; modifier; repeat expansions
- Research Division(s)
- Genetics and Gene Regulation; Bioinformatics and Computational Biology
- PubMed ID
- 42473260
- Publisher's Version
- https://doi.org/10.1002/mds.70428
- Open Access at Publisher's Site
https://doi.org/10.1002/mds.70428- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-07-23 11:46:51
Last Modified: 2026-07-23 11:47:01