A novel RFC1 repeat motif (ACAGG) in two Asia-Pacific CANVAS families

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel R...

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Published inBrain (London, England : 1878) Vol. 143; no. 10; pp. 2904 - 2910
Main Authors Scriba, Carolin K, Beecroft, Sarah J, Clayton, Joshua S, Cortese, Andrea, Sullivan, Roisin, Yau, Wai Yan, Dominik, Natalia, Rodrigues, Miriam, Walker, Elizabeth, Dyer, Zoe, Wu, Teddy Y, Davis, Mark R, Chandler, David C, Weisburd, Ben, Houlden, Henry, Reilly, Mary M, Laing, Nigel G, Lamont, Phillipa J, Roxburgh, Richard H, Ravenscroft, Gianina
Format Journal Article
LanguageEnglish
Published England Oxford University Press 01.10.2020
Subjects
Aged
Asian Continental Ancestry Group - genetics
Bilateral Vestibulopathy - complications
Bilateral Vestibulopathy - diagnosis
Bilateral Vestibulopathy - genetics
Cerebellar Ataxia - complications
Cerebellar Ataxia - diagnosis
Cerebellar Ataxia - genetics
Cohort Studies
DNA Repeat Expansion - genetics
Female
Humans
Indonesia
Male
Middle Aged
Pedigree
Replication Protein C - genetics
Indonesia
vestibular areflexia syndrome; CANVAS; RFC1; repeat expansion
neuropathy
sensory neuropathy; cerebellar ataxia
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Summary:Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is a progressive late-onset, neurological disease. Recently, a pentanucleotide expansion in intron 2 of RFC1 was identified as the genetic cause of CANVAS. We screened an Asian-Pacific cohort for CANVAS and identified a novel RFC1 repeat expansion motif, (ACAGG)exp, in three affected individuals. This motif was associated with additional clinical features including fasciculations and elevated serum creatine kinase. These features have not previously been described in individuals with genetically-confirmed CANVAS. Haplotype analysis showed our patients shared the same core haplotype as previously published, supporting the possibility of a single origin of the RFC1 disease allele. We analysed data from >26 000 genetically diverse individuals in gnomAD to show enrichment of (ACAGG) in non-European populations.
Bibliography:Carolin K. Scriba and Sarah J. Beecroft contributed equally to this work.
ISSN:0006-8950
1460-2156
DOI:10.1093/brain/awaa263