The excess of carriers in rare disorders suggests a nonpathogenic effect for most variants of uncertain significance

Medaglia, Stefano; Reig-Palou, Jaume; Bellés, Ariadna; Moreno Ruiz, Nerea; Rodríguez, Jairo; Armengol, Xavier; Aróstegui Gorospe, Juan Ignacio; Armengol i Dulcet, Lluís; Guillén, Juan José; Laayouni, Hafid, 1968-; Casals López, Ferran

doi:http://dx.doi.org/10.1111/cge.14642

The excess of carriers in rare disorders suggests a nonpathogenic effect for most variants of uncertain significance

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Medaglia S, Reig-Palou J, Bellés A, Moreno-Ruiz N, Rodríguez J, Armengol X, et al. The excess of carriers in rare disorders suggests a nonpathogenic effect for most variants of uncertain significance. Clin Genet. 2025 Mar;107(3):323-7. DOI: 10.1111/cge.14642

Abstract

Functional annotation and interpretation of genetic variants are a critical step in genetic diagnosis, as it may lead to personalized therapeutic options and genetic counseling. While the number of confirmed pathogenic genetic variants in an individual is relatively low, the number of variants of uncertain significance (VOUS) can be considerably higher, increasing the number of potential carriers of genetic disorders. Thus, reducing uncertainty and assessing the real effect of VOUS are crucial for clinical and medical genetics. In this study, we evaluated the efficacy of genetic screening technologies in accurately predicting pathogenic variants and their corresponding disease prevalence in a cohort of over 6000 healthy individuals involved in assisted reproduction programs. Using data from 305 genes associated with recessive disorders, we determined the frequency of carriers of pathogenic variants and VOUS in our dataset and compared the predicted prevalence based on this information with reported population prevalence data. The higher predicted prevalence in some disorders when considering VOUS suggests a mostly benign effect.