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

Nat Genet. 2019 Apr;51(4):649-658. doi: 10.1038/s41588-019-0372-4.

Andrea Cortese ¹, Roberto Simone ², Roisin Sullivan ^# ³, Jana Vandrovcova ^# ³, Huma Tariq ³, Wai Yan Yau ³, Jack Humphrey ³, Zane Jaunmuktane ², Prasanth Sivakumar ³, James Polke ⁴, Muhammad Ilyas ⁵, Eloise Tribollet ³, Pedro J Tomaselli ⁶, Grazia Devigili ⁷, Ilaria Callegari ⁸, Maurizio Versino ⁸ ⁹, Vincenzo Salpietro ³, Stephanie Efthymiou ³, Diego Kaski ³, Nick W Wood ³, Nadja S Andrade ¹⁰, Elena Buglo ¹¹, Adriana Rebelo ¹¹, Alexander M Rossor ³, Adolfo Bronstein ², Pietro Fratta ³, Wilson J Marques ⁶, Stephan Züchner ¹¹, Mary M Reilly ^# ³, Henry Houlden ¹² ¹³

Affiliations

1 Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK. [email protected].
2 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
3 Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
4 Neurogenetics Laboratory, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
5 Department of Biological Sciences, International Islamic University, Islamabad, Pakistan.
6 Department of Neurology, School of Medicine at Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
7 UO Neurologia I, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Milan, Italy.
8 IRCCS Mondino Foundation, Pavia, Italy.
9 Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
10 Department of Psychiatry and Behavioural Sciences, Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA.
11 Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
12 Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK. [email protected].
13 Neurogenetics Laboratory, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK. [email protected].
# Contributed equally.

PMID: 30926972 DOI: 10.1038/s41588-019-0372-4

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.

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