A population-based resource for the prioritization of rare variants of unknown significance in clinical genomics

Rare diseases represent a major public health challenge because they are often associated with severe phenotypes, yet many causal variants remain undiscovered. Founder populations provide a unique opportunity to identify disease-causing variants through the local enrichment of rare alleles. Using whole-genome sequencing data from individuals in the Saguenay-Lac-Saint-Jean population, enriched variants were identified and their founder status was assessed through identity-by-descent sharing. Variant impact was evaluated using functional prediction tools without relying on prior clinical classification. A total of 131 founder variants of interest were identified, most of which would likely have been overlooked by conventional approaches based on existing clinical annotations. We developed a web-based platform that facilitates clinician access to the latest interpretation of their genetic variants of interest. These findings demonstrate that potentially pathogenic variants can remain undetected even in extensively studied founder populations. More broadly, they highlight the value of population structure-based approaches for uncovering rare disease variants and improving the characterization of genetic disease risk across human populations.