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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 Papadimitriou, Sofia ;Gravel, Barbara ;Nachtegael, Charlotte ;De Baere, Elfride;Loeys, Bart;Vikkula, Miikka;Smits, Guillaume ;Lenaerts, Tom
Référence Rare Med Symposium(8-12-2022: Gent), Rare Med Symposium
Publication Publié, 2022-12-08

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Résumé :

Background/Aims:Reports of oligogenic cases (i.e. individuals whose disease phenotype can only be explained by the co-occurrence of multiple variants in several genes) have been rapidly increasing, in an effort to close the gap of missing genetic diagnoses. Nevertheless, the quality of this data had never been properly assessed, especially as standards and guidelines for such cases are currently missing. This work, aimed to collect all reported oligogenic cases in one database, OLIDA, assess the quality of the reported information and provide, for the first time, recommendations for their proper reporting. Methods:318 research articles reporting oligogenic cases were extracted from PubMed. Independent curators collected the relevant oligogenic information (i) from the articles and (ii) from public relevant databases. With this data, 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. The collection and assessment of this data led to the creation of OLIDA, the Oligogenic Diseases Database. Results:OLIDA contains information on 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 data revealed that the majority of papers do not provide proper genetic evidence excluding a monogenic model, while this evidence is rarely coupled with 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. Conclusion: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.