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

Medaglia, StefanoReig-Palou, JaumeBellés, AriadnaMoreno Ruiz, NereaRodríguez, JairoArmengol, XavierAróstegui Gorospe, Juan IgnacioArmengol i Dulcet, LluísGuillén, Juan JoséLaayouni, Hafid, 1968-Casals López, Ferran2025-01-242025-01-242024Medaglia 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. 2024 Nov 5. DOI: 10.1111/cge.146420009-9163http://hdl.handle.net/10230/69270Data de publicació electrònica: 05-11-2024Functional 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.application/pdfeng© 2024 The Author(s). Clinical Genetics published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.The excess of carriers in rare disorders suggests a nonpathogenic effect for most variants of uncertain significanceinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1111/cge.14642VOUSCarrier screeningFunctional annotationRecessive disordersinfo:eu-repo/semantics/openAccess