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

• Published in: Brain (London, England : 1878) Vol. 143; no. 9; pp. 2673 - 2680
• Main Authors: Beecroft, Sarah J, Cortese, Andrea, Sullivan, Roisin, Yau, Wai Yan, Dyer, Zoe, Wu, Teddy Y, Mulroy, Eoin, Pelosi, Luciana, Rodrigues, Miriam, Taylor, Rachael, Mossman, Stuart, Leadbetter, Ruth, Cleland, James, Anderson, Tim, Ravenscroft, Gianina, Laing, Nigel G, Houlden, Henry, Reilly, Mary M, Roxburgh, Richard H
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.09.2020
• Subjects: Adult; Aged; Alleles; Bilateral Vestibulopathy - diagnosis; Bilateral Vestibulopathy - ethnology; Bilateral Vestibulopathy - genetics; Cerebellar Ataxia - diagnosis; Cerebellar Ataxia - ethnology; Cerebellar Ataxia - genetics; Cohort Studies; Female; Founder Effect; Humans; Male; Middle Aged; Native Hawaiian or Other Pacific Islander - ethnology; Native Hawaiian or Other Pacific Islander - genetics; Pedigree; Replication Protein C - genetics; Māori; RFC1; CANVAS; founder effect; repeat expansion
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awaa203

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.