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

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.

Keywords: CANVAS; Māori; RFC1; founder effect; repeat expansion.

Figure 1

Pedigrees of the two multiplex families in the cohort. Asterisks indicate individuals that provided DNA for this study. A black circle inside the symbol of an unaffected individual indicates they are a CANVAS genotype carrier. (A) Family CI1 comprised Cook Island Māori individuals. (B) Family M2 comprised New Zealand Māori individuals. Although the first and second generations of family M2 were reported to be unaffected by their family, they were never formally assessed.

Figure 2

Summary of RFC1 configurations. (A) Schematic representation of the repeat alleles at the CANVAS locus, demonstrating the non-pathogenic alleles (top) and the pathogenic alleles (bottom). (B) Representative repeat-primed PCR results demonstrating the new CANVAS configuration. The typical RFC1 (AAGGG)_exp repeat pattern is seen in a Caucasian CANVAS patient (top). The novel configuration of (AAAGG)_10-20(AAGGG)_exp is shown below. The few (AAAGG) repeats at the distal end of the RFC1 pathogenic expansion were not seen with the repeat-primed PCR. (C) Representative soft-clipped reads from WGS BAM file, showing the presence of a small number of AAAGG repeats that are continuous with the distal end of the pathogenic AAGGG repeat.