Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia

Andrea Cortese, Roberto Simone, Roisin Sullivan, Jana Vandrovcova, Huma Tariq, Yau Way Yan, Jack Humphrey, Zane Jaunmuktane, Prasanth Sivakumar, James Polke, Muhammad Ilyas, Eloise Tribollet, Pedro J Tomaselli, Grazia Devigili, Ilaria Callegari, Maurizio Versino, Vincenzo Salpietro, Stephanie Efthymiou, Diego Kaski, Nick W WoodNadja S Andrade, Elena Buglo, Adriana Rebelo, Alexander M Rossor, Adolfo Bronstein, Pietro Fratta, Wilson J Marques, Stephan Züchner, Mary M Reilly, Henry Houlden

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)649-658
Number of pages10
JournalNature Genetics
Issue number4
Publication statusPublished - Apr 2019


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