Abstract
A biallelic pentanucleotide expansion in the RFC1 gene has been reported to be a common cause of late-onset ataxia. In the general population, four different repeat conformations are observed: wild type sequence AAAAG (11 repeats) and longer expansions of either AAAAG, AAAGG or AAGGG sequences. However only the biallelic AAGGG expansions were reported to cause late-onset ataxia. In this study, we aimed to assess the prevalence and nature of RFC1 repeat expansions in three cohorts of adult-onset ataxia cases: Brazilian (n = 23) and Canadian (n = 26) cases that are negative for the presence of variants in other known ataxia-associated genes, as well as a cohort of randomly selected Canadian cases (n = 128) without regard to a genetic diagnosis. We identified the biallelic AAGGG expansion in only one Brazilian family which presented two affected siblings, and in one Canadian case. We also observed two new repeat conformations, AAGAG and AGAGG, which suggests the pentanucleotide expansion sequence has a dynamic nature. To assess the frequency of these new repeat conformations in the general population, we screened 163 healthy individuals and observed the AAGAG expansion to be more frequent in cases than in control individuals. While additional studies will be necessary to asses the pathogenic impact of biallelic genotypes that include the novel expanded conformations, their occurrence should nonetheless be examined in future studies.
Highlights
Autosomal recessive cerebellar ataxias regroup a number of heterogenous neurodegenerative diseases
Cortese and colleagues established the biallelic expansion of an AAGGG pentanucleotide repeat located in the second intron of the RFC1 gene to be a frequent cause of late-onset recessive ataxia; this particular expansion was reported to explain over 20% of sporadic ataxia in a cohort of Caucasian cases (Cortese et al, 2019)
Long-range PCR and Sanger sequencing subsequently revealed one of these two individuals to carry a biallelic AAAGG expansion; the same biallelic expansion was observed in his sister. It appears that expanded AAAGG repeat expansion can sometimes mimic the AAGGG expansion when an assessment is made only by repeat-primed polymerase chain reaction (RP-PCR), under such a context the results can lead to a misinterpretation of the true nature of the repeat expansion
Summary
Autosomal recessive cerebellar ataxias regroup a number of heterogenous neurodegenerative diseases. RFC1 Repeat in New Cohorts and Conformations ataxia of Charlevoix-Saguenay, ataxia with vitamin E deficiency, autosomal recessive cerebellar ataxia types 1 and 2, and ataxia with oculomotor apraxia types 1 and 2 (Noreau et al, 2013). Cortese and colleagues established the biallelic expansion of an AAGGG pentanucleotide repeat located in the second intron of the RFC1 gene (hg19/GRCh37, chr4:39,350,045-39,350,103) to be a frequent cause of late-onset recessive ataxia; this particular expansion was reported to explain over 20% of sporadic ataxia in a cohort of Caucasian cases (Cortese et al, 2019). A total of four distinct intronic repeat conformations were identified: AAAAG11, the wild-type sequence, and longer expansions of AAAAGn, AAAGGn, and AAGGGn. The configuration with the AAGGG pentanucleotide was shown to be the only disease-causing conformation of the expansion, ranging in size from 600 to 2,000 repeats
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