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Toward reporting standards for the pathogenicity of variant combinations involved in multilocus/oligogenic diseases

par Papadimitriou, Sofia ;Gravel, Barbara ;Nachtegael, Charlotte ;De Baere, Elfride;Loeys, Bart;Vikkula, Miikka ;Smits, Guillaume ;Lenaerts, Tom
Référence Human Genetics and Genomics Advances, 4, 1, page (100165)
Publication Publié, 2023-01

Article révisé par les pairs

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Résumé :

Although 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. During a large curation process conducted on 318 research articles presenting oligogenic variant combinations, we encountered several recurring issues concerning their proper reporting and pathogenicity assessment. These mainly concern the absence of strong evidence that refutes a monogenic model and the lack of a proper genetic and functional assessment of the joint effect of the involved variants. With the increasing accumulation of such cases, it has become essential to develop standards and guidelines on how these oligogenic/multilocus variant combinations should be interpreted, validated, and reported in order to provide high-quality data and supporting evidence to the scientific community.