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

Abstract

Repeat expansion disorders (REDs) are a class of genetic disease, most of which cause neurological or neurodevelopmental phenotypes. Recent improvements in repetitive sequence detection suggest that REDs are collectively more common than previous estimates. Several REDs occur in Quebec at exceptional frequencies, due to founder effects which have shaped the province’s genetic landscape. Because these disorders are clinically heterogeneous and difficult to diagnose, their true prevalence in the province remains largely unknown. By using whole-genome, exome, and RNA-sequencing data from CARTaGENE (CaG), a prospective Quebec population-based cohort, we characterized 13 RED loci as well as two genes associated to non-repeat neurological disorders, autosomal recessive cerebellar ataxia type 1 (ARCA1) and hereditary spastic paraplegia 11 (HSP11). We estimated carrier and expansion frequencies of premutation and full expansion alleles, finding that FXN, DMPK and FGF14 exhibited the highest values in Quebec. Assuming Hardy-Weinberg equilibrium, we calculated a genetic prevalence of 55.28 per 100,000 for SCA27B, a disorder for which prevalence estimates are lacking. Several additional REDs’ genetic prevalences were estimated up to 6.5 times higher than previously reported figures, indicating possible underdiagnosis or incomplete penetrance. Other RED genetic prevalences in CaG remained comparable to reported values, indicating that the founder effect acts on specific loci rather than across all repeat expansions. These findings highlight the REDs for which clinical resources should be prioritized in the province. Candidate founder variants associated with ARCA1 and HSP11 were identified by an enrichment analysis comparing CaG allele frequencies to the gnomAD Non-Finnish European cohort, and we report province-wide genetic prevalence estimates for both conditions. Using CaG’s sequencing data, we established a genetic profile of rare neurological disorders in Quebec. These results provide valuable information for the development of genetic screening and diagnosis strategies for rare neurological diseases.