Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.
Cortese, Andrea Simone, Roberto Sullivan, Roisin Vandrovcova, Jana Tariq, Huma Yau, Wai Yan Humphrey, Jack Jaunmuktane, Zane Sivakumar, Prasanth Polke, James Ilyas, Muhammad Tribollet, Eloise Tomaselli, Pedro J Devigili, Grazia Callegari, Ilaria Versino, Maurizio Salpietro, Vincenzo Efthymiou, Stephanie Kaski, Diego Wood, Nick W Andrade, Nadja S Buglo, Elena Rebelo, Adriana Rossor, Alexander M Bronstein, Adolfo Fratta, Pietro Marques, Wilson J Züchner, Stephan Reilly, Mary M Houlden, Henry
Cortese A, etal., Nat Genet. 2019 Apr;51(4):649-658. doi: 10.1038/s41588-019-0372-4. Epub 2019 Mar 29.
Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG)11 allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia.