FIND: a software tool for identifying population-enriched pathogenic variants in gnomAD

Abstract

Founder mutations are variants that arose in a single ancestor and became enriched in a descendant population through a bottleneck and endogamy. Identification of pathogenic founder mutations has facilitated efficient targeted screening. More broadly, even without confirmed founder status, identifying pathogenic variants that are enriched within specific populations reveals population-specific disease burden. However, many such variants remain hidden in plain sight within existing datasets. To address this gap, we developed FIND (Founder candidates hidden IN Data), a web tool that identifies variants in gnomAD with frequencies >0.00008 in one ancestry group and at least tenfold higher than in all others (after zeroing populations with fewer than five observed alleles). The search is restricted to looking at pathogenic, likely pathogenic, and predicted loss-of-function variants. Testing FIND on the genes FLNC, TMEM127, MYH7, BRCA1, and BRCA2 confirmed its utility and functionality by identifying twelve well-known founder or population-enriched mutations and, as candidate founders with unconfirmed founder status, five variants previously reported as recurrent in a population but never compared across populations and three not previously reported as population-enriched. Variants enriched in African American and admixed American populations were validated with the All of Us database, highlighting the utility of this approach for populations historically underrepresented in genetic studies. The source code is freely available at https://github.com/aacoder105/FIND under an MIT license, with a web interface at https://ethnic-variant-mutation-finder.onrender.com/.