Rare diseases load through the study of a regional population

Rare genetic diseases impact many people worldwide and are challenging to diagnose. In this study, we introduce a novel regional population cohort approach to identify pathogenic variants that occur more frequently within specific populations and are of clinical interest. We utilized a cohort from Quebec, including the Saguenay-Lac-Saint-Jean region, which is known for its founder effect and higher frequency of certain pathogenic variants. By analyzing both the frequency of these variants and their origin through shared identical-by-descent segments, we validated 38 variants previously reported as being more common due to the founder effect. Additionally, we identified 42 unreported founder variants in Quebec or the Saguenay-Lac-Saint-Jean, some with carrier rates estimates as high as 1/22. We also observed a greater deleterious mutational load for the studied variants in individuals from the Saguenay-Lac-Saint-Jean compared to other urban Quebec regions. These findings were brought to the clinic where 12 pathogenic variants were detected in patients, including 3 that are responsible for very severe diseases and could be considered for inclusion in a carrier test for the Saguenay-Lac-Saint-Jean population. This study highlights the potential underestimation of rare disease prevalence and presents a population-based approach that could aid clinicians in their diagnostic efforts and patients management.