| Title: | DNA Repair Pathway Variants Are Enriched in Individuals with Biallelic AAGGG CANVAS and RFC1-Related Disease |
| Journal: | Movement Disorders |
| Published: | 19 Jul 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42473260/ |
| DOI: | https://doi.org/10.1002/mds.70428 |
Publication 21348
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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.</p>
OBJECTIVE: To determine whether polygenic risk factors influence incomplete penetrance in RFC1-related disease.</p>
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.</p>
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).</p>
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.</p>
14 Authors
- Xuemin Wang
- Liam G. Fearnley
- Kayli C. Davies
- Penny Snell
- Stuart Lee
- Victoria E. Jackson
- Justin Read
- Michael Milton
- Ian H. Harding
- Martin B. Delatycki
- David J. Szmulewicz
- Paul J. Lockhart
- Melanie Bahlo
- Haloom Rafehi
1 Application
| Application ID | Title |
|---|---|
| 36610 | Exploring the genetic basis of healthy development and ageing: gene discovery and methods development. |
Enabling scientific discoveries that improve human health