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Bourassa, C. V.

Publications and source records attributed to Bourassa, C. V..

2 recordsLinked to original sources
bioRxiv2019

Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study. Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 x 10-5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD.

genetics↗
bioRxiv2019

Investigation of the pathogenic RFC1 repeat expansion in a Canadian and a Brazilian ataxia cohort: identification of novel conformations

A homozygous pentanucleotide expansion in the RFC1 gene has been shown to be a common cause of late-onset ataxia. In the general population a total of four different repeat conformations have been observed: a wild type sequence AAAAG (11 repeats), and longer expansions of AAAAG, AAAGG and AAGGG sequences. However, in ataxia cases only the AAGGG expansion has been shown to be pathogenic. In this study, we assessed the prevalence and nature of RFC1 repeat expansions in three adult-onset ataxia cohorts: Brazilian (n = 23) and Canadian (n = 26) cases that tested negative for other known ataxia mutations, as well as a cohort of randomly selected Canadian cases (n = 128) without regard to a genetic diagnosis. We identified the homozygous AAGGG pathogenic expansion in only one Brazilian family with two affected siblings, and in one Canadian case. The RFC1 expansion may therefore not be a common cause of adult-onset ataxia in these populations. Interestingly we observed two new repeat motifs, AAGAG and AGAGG, which indicates the dynamic nature of the pentanucleotide expansion sequence. To assess the frequency of these two new repeat conformations in the general population we screened 163 healthy individuals. These novel motifs were more frequent in patients versus controls. While we cannot be certain that the homozygous genotypes of the novel expanded conformations are pathogenic, their occurrence should nonetheless be taken into consideration in future studies.

genetics↗