Abstract
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.
Published: April 2019
Authors
Andrea Cortese1, Roberto Simone2, Roisin Sullivan#3, Jana Vandrovcova#3, Huma Tariq3, Wai Yan Yau3, Jack Humphrey3, Zane Jaunmuktane2, Prasanth Sivakumar3, James Polke4, Muhammad Ilyas5, Eloise Tribollet3, Pedro J Tomaselli6, Grazia Devigili7, Ilaria Callegari8, Maurizio Versino89, Vincenzo Salpietro3, Stephanie Efthymiou3, Diego Kaski3, Nick W Wood3, Nadja S Andrade10, Elena Buglo11, Adriana Rebelo11, Alexander M Rossor3, Adolfo Bronstein2, Pietro Fratta3, Wilson J Marques6, Stephan Züchner11, Mary M Reilly#3, Henry Houlden1213
Erratum in
Cortese A, Simone R, Sullivan R, Vandrovcova J, Tariq H, Yau WY, Humphrey J, Jaunmuktane Z, Sivakumar P, Polke J, Ilyas M, Tribollet E, Tomaselli PJ, Devigili G, Callegari I, Versino M, Salpietro V, Efthymiou S, Kaski D, Wood NW, Andrade NS, Buglo E, Rebelo A, Rossor AM, Bronstein A, Fratta P, Marques WJ, Züchner S, Reilly MM, Houlden H.Nat Genet. 2019 May;
Published: May 2019