RFC1-Related Disease Molecular and Clinical Insights

In 2019, a biallelic pentanucleotide repeat expansion in the gene encoding replication factor C subunit 1 (RFC1) was reported as a cause of cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS). In addition, biallelic expansions were shown to account for up to 22% of cases with late-onset ataxia. Since this discovery, the phenotypic spectrum reported to be associated with RFC1 expansions has extended beyond the initial conditions to include pure cerebellar ataxia, isolated somatosensory impairment, combinations of the 2, and parkinsonism, leading to a potentially broad differential diagnosis. Genetic studies suggest RFC1 expansions may be the most common genetic cause of ataxia and are likely underdiagnosed. This review summarizes the current molecular and clinical knowledge of RFC1-related disease, with a focus on the evaluation of recent phenotype associations and highlighting the current challenges in clinical pathways to diagnosis and molecular testing.