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 causing Mendelian diseases that occur more frequently within specific populations and are of clinical interest for carrier testing. We utilized a cohort from Quebec, including the Saguenay-Lac-Saint-Jean region, which is known for its founder effect followed by a rapid expansion and higher frequency of certain pathogenic variants. By analyzing both their frequency and origin through shared identical-by-descent segments, we identified founder variants. We calculated and compared their frequency in individuals originating from the Saguenay-Lac-Saint-Jean and from other urban Quebec regions. We validated 38 previously reported variants as being more common due to the founder effect and population expansion. Additionally, we identified 42 unreported founder variants in Quebec or 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 diagnosed patients. Five variants found in this study 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.