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A Māori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele

Beecroft, SJ; Cortese, A; Sullivan, R; Yau, WY; Dyer, Z; Wu, TY; Mulroy, E; ... Roxburgh, RH; + view all (2020) A Māori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele. Brain , 143 (9) pp. 2673-2680. 10.1093/brain/awaa203. Green open access

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Abstract

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative disease with onset in mid- to late adulthood. The genetic basis for a large proportion of Caucasian patients was recently shown to be the biallelic expansion of a pentanucleotide (AAGGG)n repeat in RFC1. Here, we describe the first instance of CANVAS genetic testing in New Zealand Māori and Cook Island Māori individuals. We show a novel, possibly population-specific CANVAS configuration (AAAGG)10-25(AAGGG)exp, which was the cause of CANVAS in all patients. There were no apparent phenotypic differences compared with European CANVAS patients. Presence of a common disease haplotype among this cohort suggests this novel repeat expansion configuration is a founder effect in this population, which may indicate that CANVAS will be especially prevalent in this group. Haplotype dating estimated the most recent common ancestor at ∼1430 CE. We also show the same core haplotype as previously described, supporting a single origin of the CANVAS mutation.

Type: Article
Title: A Māori specific RFC1 pathogenic repeat configuration in CANVAS, likely due to a founder allele
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/brain/awaa203
Publisher version: https://doi.org/10.1093/brain/awaa203
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: CANVAS, repeat expansion, RFC1, founder effect, Māori
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10110961
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