The Excess of Carriers in Rare Disorders Suggests a Nonpathogenic Effect for Most Variants of Uncertain Significance
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.
Authors
- Nerea Moreno‐Ruiz (ORCID: https://orcid.org/0000-0002-9636-0179)
- Juan José Guillén
- Lluı́s Armengol (ORCID: https://orcid.org/0000-0002-7141-1865)
- Ferrán Casals (ORCID: https://orcid.org/0000-0002-8941-0369)
- Juan I. Aróstegui (ORCID: https://orcid.org/0000-0003-4757-504X)
- Xavier Armengol (ORCID: https://orcid.org/0000-0002-0312-0396)
- Hafid Laayouni (ORCID: https://orcid.org/0000-0003-1297-5078)
- Jaume Reig‐Palou (ORCID: https://orcid.org/0000-0002-8270-7004)
- Ariadna Bellés
- J.L. Rodriguez
- Stefano Medaglia
Institutions
- Universitat Pompeu Fabra (ES)
- University of Trento (IT)
- Instituto de Salud Carlos III (ES)
- Barcelona Biomedical Research Park (ES)
- Pasqual Maragall Foundation (ES)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- Institut de Biologia Evolutiva (ES)
- Oryzon Genomics (Spain) (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Instituto de Investigación de Enfermedades Raras (ES)
- Quantitative Genomics Medicine Laboratories (qGenomics)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Clinical Genetics
- Published
- 2024-11-05
- DOI
- https://doi.org/10.1111/cge.14642
- Citations
- 1
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 0.55
Funders
- Generalitat de Catalunya
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- European Regional Development Fund
- Agencia Estatal de Investigación