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

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.