Toward reporting standards for the pathogenicity of variant combinations involved in multilocus/oligogenic diseases
Sofia Papadimitriou,
Barbara Gravel,
Charlotte Nachtegael,
Elfride De Baere,
Bart Loeys,
Miikka Vikkula,
Guillaume Smits,
Tom Lenaerts
Affiliations
Sofia Papadimitriou
Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium; Machine Learning Group, Université Libre de Bruxelles, 1050 Brussels, Belgium; Artificial Intelligence Laboratory, Vrije Universiteit Brussel, 1050 Brussels, Belgium; Corresponding author
Barbara Gravel
Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium; Machine Learning Group, Université Libre de Bruxelles, 1050 Brussels, Belgium; Artificial Intelligence Laboratory, Vrije Universiteit Brussel, 1050 Brussels, Belgium
Charlotte Nachtegael
Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium; Machine Learning Group, Université Libre de Bruxelles, 1050 Brussels, Belgium
Elfride De Baere
Center for Medical Genetics, Ghent University Hospital, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
Bart Loeys
Center for Medical Genetics, Antwerp University Hospital/University of Antwerp, 2650 Antwerp, Belgium
Miikka Vikkula
Human Molecular Genetics, de Duve Institute, UCLouvain, Brussels, Belgium
Guillaume Smits
Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium; Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, 1070 Brussels, Belgium; Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, 1020 Brussels, Belgium
Tom Lenaerts
Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium; Machine Learning Group, Université Libre de Bruxelles, 1050 Brussels, Belgium; Artificial Intelligence Laboratory, Vrije Universiteit Brussel, 1050 Brussels, Belgium; Corresponding author
Summary: 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.
