Quebec population carries unusually high levels of rare neurological disease variants

A population-based genomic study of Quebec found that several repeat-expansion disorders and other rare inherited neurological conditions are more frequent in the province than global estimates suggest, with the strongest signals emerging for spinocerebellar ataxia 27B, myotonic dystrophy type 1, Friedreich’s ataxia and the C9orf72 expansion associated with amyotrophic lateral sclerosis and frontotemporal dementia. Researchers analyzed sequencing data from 3,189 participants in the prospective CARTaGENE cohort, estimating the prevalence of disease-associated alleles without relying on clinical case registries. The findings indicate that founder history has shaped Quebec’s genetic landscape unevenly, concentrating some dangerous variants while leaving others at frequencies closer to those seen elsewhere.

The study examined 19 repeat-expansion loci, identifying premutation or fully expanded disease alleles at 13 of them. The largest numbers of at-risk alleles occurred in FXN, associated with Friedreich’s ataxia; DMPK, associated with myotonic dystrophy type 1; FGF14, associated with spinocerebellar ataxia 27B; FMR1, associated with fragile X-related disorders; and TBP, associated with spinocerebellar ataxia 17. Expansion alleles were also found in C9orf72, HTT, JPH3, ATN1, ATXN1, ATXN2 and ATXN7. No disease-associated premutations or expansions were detected at six loci in the cohort: ATXN3, CACNA1A, NOTCH2NL, PABPN1, PPP2R2B and RFC1. The distribution shows that Quebec’s founder effects have not raised the frequency of every repeat expansion uniformly.

For FXN, the estimated frequency of carriers of a fully pathogenic expansion was one in 136, while premutation carriers occurred at one in 121. Among the autosomal dominant disorders, FGF14 and C9orf72 had the highest estimated pathogenic expansion frequencies, both at one in 546. DMPK followed at one in 728, while its premutation frequency reached one in 115, the highest estimated carrier frequency for any variant class examined. FGF14 premutation carriers occurred at one in 218. TBP premutations were found at one in 273, and HTT and JPH3 premutations at one in 728. These are estimates of the prevalence of disease-associated alleles in the sampled population, not counts of diagnosed patients, because the CARTaGENE participants had not received diagnoses of rare neurological diseases when they were recruited.

Using Hardy-Weinberg equilibrium, the investigators estimated genetic prevalence for disorders in which fully pathogenic expansions were detected. SCA27B and ALS/FTD each reached 55.28 cases per 100,000 people under assumptions of full penetrance. Based on 78,200 births recorded in Quebec in 2025, this corresponds to approximately 43 expected affected births per year for each disorder. SCA27B is a recently described condition for which a worldwide prevalence estimate was lacking, while the ALS/FTD estimate was almost five times the reported ALS prevalence range of 5 to 12 per 100,000 and six times the reported FTD prevalence of 9.17 per 100,000. These genetic estimates may reflect founder effects, but they may also be influenced by underdiagnosis or incomplete penetrance.

Myotonic dystrophy type 1 had an estimated genetic prevalence of 32.64 per 100,000, 6.5 times the global prevalence of 5 per 100,000 reported in the study, though it was lower than the 158 per 100,000 previously reported for the Saguenay–Lac-Saint-Jean region. The estimate corresponds to roughly 26 expected affected births annually in Quebec. Friedreich’s ataxia was estimated at 1.34 per 100,000, 2.7 times the global figure of 0.5 per 100,000, while spinocerebellar ataxia 2 was estimated at 1.94 per 100,000, near the upper end of the reported 1 to 2 per 100,000 range. The C9orf72 result was particularly striking because the expansion is an important cause of neurodegeneration and had previously been identified in French-Canadian families.

Population-structure analyses did not pin the DMPK or FXN carriers to a single region of Quebec. Some fell within an identity-by-descent cluster associated with the Saguenay founder effect, but only 21.5% of that cluster was recruited in Saguenay; the remainder came from across the province. The pattern therefore suggests shared ancestry from early founder populations rather than a Saguenay-specific origin. It also indicates that DMPK premutation carriers are present outside the region where genetic counselling and predictive testing have long been available. The study did not directly assess the effectiveness or cost of extending services, but it identified the geographic distribution of carriers relevant to any such planning.

Beyond repeat expansions, the researchers searched for pathogenic variants in SYNE1, which cause autosomal recessive cerebellar ataxia type 1, and SPG11, which causes hereditary spastic paraplegia type 11. They found seven pathogenic SYNE1 variants and three pathogenic SPG11 variants across the cohort. All SYNE1 alleles were more frequent in CARTaGENE than in the gnomAD Non-Finnish European group, with six of the seven significantly enriched by a one-sided Fisher’s exact test. All three SPG11 variants were also significantly enriched. The most frequent SYNE1 variant was c.14211dup, while c.1478_1482del was the most common of the SPG11 variants. Such enrichment is consistent with the distinct founder history of Quebec’s population, but the comparison with a European reference group does not by itself establish that every variant arose from a specific Quebec founder.

Combining the SYNE1 variants, the investigators estimated ARCA1 genetic prevalence at 3.93 per 100,000, equivalent to about 3.08 expected new cases per year. The corresponding SPG11 estimate was 0.25 per 100,000, or about 0.19 expected new cases annually. These were among the first province-wide genetic prevalence estimates for the two conditions. The HSP11 value was lower than a previously reported minimum of 0.56 per 100,000 in Eastern Quebec, whereas the ARCA1 estimate exceeded the Eastern Quebec minimum of 2.67 per 100,000. The differences may reflect the metropolitan areas sampled by CARTaGENE and its omission of Beauce, where ARCA1 is concentrated. As with the repeat expansions, these figures describe expected disease-associated genotypes rather than clinically observed cases.

Several limitations constrain the precision and interpretation of the results. Short-read whole-genome sequencing cannot always measure very large repeat expansions accurately; long-read sequencing would characterize repeat size and composition more directly, reducing the possibility that an allele is classified on the wrong side of a pathogenic or reduced-penetrance threshold. The whole-genome subset included 2,184 participants, and the prevalence estimates have wide confidence intervals, especially for rare variants. The researchers used lower confidence bounds for dominant and X-linked estimates to limit potential overestimation from small samples. The cohort also sampled metropolitan areas rather than every founder region, and all prevalence calculations assumed Hardy-Weinberg equilibrium and full penetrance. The results therefore provide a population-level map of rare disease risk in Quebec, but they do not establish how many people currently have symptoms, how penetrance varies with age, or whether expanded screening would improve outcomes.

Subject of Research: Population-level prevalence of repeat-expansion and founder-associated rare neurological disorders in Quebec

Article Title: Genetic prevalence of repeat expansion and other rare neurological disorders in the Quebec population

Article References: De Mori, A., Labrecque, M., Triassi, V., Audet, S., Pelletier, J., Lai, A., La Piana, R., Duquette, A., Bhérer, C., & Tetreault, M. (2026). Genetic prevalence of repeat expansion and other rare neurological disorders in the Quebec population. Frontiers in Genetics, 17, Article 1964104. https://doi.org/10.3389/fgene.2026.1964104

Image Credits: AI Generated

DOI: 10.3389/fgene.2026.1964104

Keywords: Quebec genetics, repeat expansion disorders, rare neurological diseases, founder effects, population sequencing, CARTaGENE cohort, spinocerebellar ataxia, myotonic dystrophy, genetic prevalence, neurogenomics, Genetic, prevalence