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Publications

Journal Article Ppublish

PubMed: 39501598 DOI: 10.1111/cge.14642

The Excess of Carriers in Rare Disorders Suggests a Nonpathogenic Effect for Most Variants of Uncertain Significance.

Clin Genet 107(3):323-327

Authors: Stefano Medaglia, Jaume Reig-Palou, Ariadna Bellés, Nerea Moreno-Ruiz, Jairo Rodríguez, Xavier Armengol, Juan Ignacio Aróstegui, Lluís Armengol, Juan José Guillén, Hafid Laayouni, Ferran Casals

Affiliations

  • Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain. Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
  • Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.
  • Clínica EUGIN, Barcelona, Spain.
  • Institut de Biologia Evolutiva (UPF-CSIC), department of Medicine and Life Sciences, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.
  • Quantitative Genomic Medicine Laboratories (qGenomics), Esplugues del Llobregat, Barcelona, Spain.
  • Departament d'Immunologia, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
  • Escola de Medicina, Universitat de Barcelona, Barcelona, Spain.
  • BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain.
  • Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
  • Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.
  • Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.

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.

MeSH

Prevalence, Genetics, Medical