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The importance of good data quality and proper pathogenicity reporting in the medical genetics field: the case of oligogenic diseases

par Nachtegael, Charlotte ;Papadimitriou, Sofia ;Gravel, Barbara ;De Baere, Elfride;Loeys, Bart;Vikkula, Miikka;Smits, Guillaume ;Lenaerts, Tom
Référence Annual Biocuration Conference(16: 24-26/04/2023: Padua, Italie)
Publication Publié, 2023-04

Abstract de conférence

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Résumé :

though standards and guidelines for the interpretation of variants identified in genes that cause Mendelian disorders have been developed, this is not the case for more complex genetic models including variant combinations in multiple genes. 318 research articles reporting oligogenic cases were extracted from PubMed. A transparent curation protocol was developed assigning a confidence score to each oligogenic case based on the amount of pathogenic evidence at the genetic and functional level, based on the relevant oligogenic information collected by independent curators (i) from the articles and (ii) from public relevant databases. The collection and assessment of this data led to the creation of OLIDA, the Oligogenic Diseases Database. OLIDA contains information on 1229 oligogenic cases linked to 177 different genetic diseases. Each instance is linked with a confidence score depicting the quality of the associated genetic and functional pathogenic evidence. The curation process revealed that the majority of papers do not provide proper genetic evidence refuting a monogenic model, and rarely perform functional experiments for confirmation. Our recommendations stress the necessity of fulfilling both conditions. The use of multiple extended pedigrees showing a clear segregation of the reported variants, control cohorts of a suitable size, as well as functional experiments showing the synergistic effect of the involved variants are essential for this purpose. With our work we reveal the recurrent issues on the reporting of oligogenic cases and stress the need for the development of standards in the field. As the number of papers identifying oligogenic causes to disease is increasing rapidly, initiating this discussion is imperative.