Journal
NATURE GENETICS
Volume 51, Issue 4, Pages 649-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-019-0372-4
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Funding
- Inherited Neuropathies Consortium (INC) part of the National Institutes of Health Rare Diseases Clinical Research Network (RDCRN) [U54NS065712]
- Wellcome Trust [204841/Z/16/Z, 110043/Z/15/Z, 165908]
- Rosetree Trust
- Ataxia UK
- MSA Trust
- Brain Research UK
- Muscular Dystrophy UK
- Muscular Dystrophy Association
- Higher Education Commission of Pakistan
- Medical Research Council (MRC), MRC Centre grant [G0601943]
- National Institutes of Neurological Diseases and Stroke
- Office of Rare Diseases [U54NS065712]
- INC part of the National Center for Advancing Translational Sciences (NCATS) RDCRN [U54NS065712]
- NCATS
- National Institute of Neurological Disorders and Stroke
- National Institutes of Health (NIH) [4R01NS075764]
- National Institute for Health Research University College London Hospitals Biomedical Research Centre [176718]
- Medical Research Council
- Brain Tumour Research
- NIH
- Muscular Dystrophy Association USA [171011]
- MRC/MNDA CSF [MR/M008606/1]
- MRC [1936823, MR/N004272/1, G0701018, MR/M008606/1, G0802760, MR/S006508/1, MR/J004758/1, G1001253, G108/638, MR/S01165X/1, G1100578] Funding Source: UKRI
- Wellcome Trust [110043/Z/15/Z] Funding Source: researchfish
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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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