{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T23:08:00Z","timestamp":1772492880411,"version":"3.50.1"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"W1","license":[{"start":{"date-parts":[[2019,5,31]],"date-time":"2019-05-31T00:00:00Z","timestamp":1559260800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["27.002.53.01.4524"],"award-info":[{"award-number":["27.002.53.01.4524"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,7,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A tremendous amount of DNA sequencing data is being produced around the world with the ambition to capture in more detail the mechanisms underlying human diseases. While numerous bioinformatics tools exist that allow the discovery of causal variants in Mendelian diseases, little to no support is provided to do the same for variant combinations, an essential task for the discovery of the causes of oligogenic diseases. ORVAL (the Oligogenic Resource for Variant AnaLysis), which is presented here, provides an answer to this problem by focusing on generating networks of candidate pathogenic variant combinations in gene pairs, as opposed to isolated variants in unique genes. This online platform integrates innovative machine learning methods for combinatorial variant pathogenicity prediction with visualization techniques, offering several interactive and exploratory tools, such as pathogenic gene and protein interaction networks, a ranking of pathogenic gene pairs, as well as visual mappings of the cellular location and pathway information. ORVAL is the first web-based exploration platform dedicated to identifying networks of candidate pathogenic variant combinations with the sole ambition to help in uncovering oligogenic causes for patients that cannot rely on the classical disease analysis tools. ORVAL is available at https:\/\/orval.ibsquare.be.<\/jats:p>","DOI":"10.1093\/nar\/gkz437","type":"journal-article","created":{"date-parts":[[2019,5,9]],"date-time":"2019-05-09T15:21:10Z","timestamp":1557415270000},"page":"W93-W98","source":"Crossref","is-referenced-by-count":60,"title":["ORVAL: a novel platform for the prediction and exploration of disease-causing oligogenic variant combinations"],"prefix":"10.1093","volume":"47","author":[{"given":"Alexandre","family":"Renaux","sequence":"first","affiliation":[{"name":"Interuniversity Institute of Bioinformatics in Brussels, Universit\u00e9 Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium"},{"name":"Machine Learning Group, Universit\u00e9 Libre de Bruxelles, 1050 Brussels, Belgium"},{"name":"Artificial Intelligence lab, Vrije Universiteit Brussel, 1050 Brussels, Belgium"}]},{"given":"Sofia","family":"Papadimitriou","sequence":"additional","affiliation":[{"name":"Interuniversity Institute of Bioinformatics in Brussels, Universit\u00e9 Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium"},{"name":"Machine Learning Group, Universit\u00e9 Libre de Bruxelles, 1050 Brussels, Belgium"},{"name":"Artificial Intelligence lab, Vrije Universiteit Brussel, 1050 Brussels, Belgium"}]},{"given":"Nassim","family":"Versbraegen","sequence":"additional","affiliation":[{"name":"Interuniversity Institute of Bioinformatics in Brussels, Universit\u00e9 Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium"},{"name":"Machine Learning Group, Universit\u00e9 Libre de Bruxelles, 1050 Brussels, Belgium"}]},{"given":"Charlotte","family":"Nachtegael","sequence":"additional","affiliation":[{"name":"Interuniversity Institute of Bioinformatics in Brussels, Universit\u00e9 Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium"},{"name":"Machine Learning Group, Universit\u00e9 Libre de Bruxelles, 1050 Brussels, Belgium"}]},{"given":"Simon","family":"Boutry","sequence":"additional","affiliation":[{"name":"Interuniversity Institute of Bioinformatics in Brussels, Universit\u00e9 Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium"},{"name":"Laboratory of Human Molecular Genetics, de Duve Institute, UCLouvain, 1200 Brussels, Belgium"}]},{"given":"Ann","family":"Now\u00e9","sequence":"additional","affiliation":[{"name":"Interuniversity Institute of Bioinformatics in Brussels, Universit\u00e9 Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium"},{"name":"Artificial Intelligence lab, Vrije Universiteit Brussel, 1050 Brussels, Belgium"}]},{"given":"Guillaume","family":"Smits","sequence":"additional","affiliation":[{"name":"Interuniversity Institute of Bioinformatics in Brussels, Universit\u00e9 Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium"},{"name":"H\u00f4pital Universitaire des Enfants Reine Fabiola, 1020 Brussels, Belgium"},{"name":"Center of Human Genetics, H\u00f4pital Erasme, 1070 Brussels, Belgium"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3645-1455","authenticated-orcid":false,"given":"Tom","family":"Lenaerts","sequence":"additional","affiliation":[{"name":"Interuniversity Institute of Bioinformatics in Brussels, Universit\u00e9 Libre de Bruxelles-Vrije Universiteit Brussel, 1050 Brussels, Belgium"},{"name":"Machine Learning Group, Universit\u00e9 Libre de Bruxelles, 1050 Brussels, Belgium"},{"name":"Artificial Intelligence lab, Vrije Universiteit Brussel, 1050 Brussels, Belgium"}]}],"member":"286","published-online":{"date-parts":[[2019,5,31]]},"reference":[{"key":"2019062808325089100_B1","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/nrg3031","article-title":"Exome sequencing as a tool for Mendelian disease gene discovery","volume":"12","author":"Bamshad","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"2019062808325089100_B2","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.ajhg.2015.06.009","article-title":"The genetic basis of mendelian Phenotypes: Discoveries, challenges, and opportunities","volume":"97","author":"Chong","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"2019062808325089100_B3","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2019062808325089100_B4","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1093\/bioinformatics\/btu703","article-title":"DANN: a deep learning approach for annotating the pathogenicity of genetic variants","volume":"31","author":"Quang\u00a0Chen","year":"2015","journal-title":"Bioinformatics"},{"key":"2019062808325089100_B5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nrg3253","article-title":"Computational tools for prioritizing candidate genes: boosting disease gene discovery","volume":"13","author":"Moreau","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"2019062808325089100_B6","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1186\/s13059-016-1107-9","article-title":"The continuum of causality in human genetic disorders","volume":"17","author":"Katsanis","year":"2016","journal-title":"Genome Biol."},{"key":"2019062808325089100_B7","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1111\/cge.13150","article-title":"Digenic inheritance and genetic modifiers","volume":"93","author":"Deltas","year":"2018","journal-title":"Clin. Genet."},{"key":"2019062808325089100_B8","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/978-3-540-37654-5_8","article-title":"Oligogenic Disease","volume-title":"Vogel and Motulsky\u2019s Human Genetics: Problems and Approaches","author":"Robinson","year":"2010","edition":"4"},{"key":"2019062808325089100_B9","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.cell.2011.09.008","article-title":"Clan genomics and the complex architecture of human disease","volume":"147","author":"Lupski","year":"2011","journal-title":"Cell"},{"key":"2019062808325089100_B10","doi-asserted-by":"crossref","first-page":"R65","DOI":"10.1093\/hmg\/ddh092","article-title":"The oligogenic properties of Bardet-Biedl syndrome","volume":"13","author":"Katsanis","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"2019062808325089100_B11","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1159\/000357054","article-title":"Update on the genetics of bardet-biedl syndrome","volume":"5","author":"M\u2019Hamdi","year":"2014","journal-title":"Mol. Syndromol."},{"key":"2019062808325089100_B12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1111\/j.1749-6632.2010.05879.x","article-title":"Modifier genes in Mendelian disorders: the example of cystic fibrosis","volume":"1214","author":"Cutting","year":"2010","journal-title":"Ann. N.Y. Acad. Sci."},{"key":"2019062808325089100_B13","doi-asserted-by":"crossref","first-page":"e394","DOI":"10.1038\/tp.2014.38","article-title":"Towards a molecular characterization of autism spectrum disorders: an exome sequencing and systems approach","volume":"4","author":"An","year":"2014","journal-title":"Transl. Psychiatry"},{"key":"2019062808325089100_B14","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/nrg910","article-title":"Beyond Mendel: an evolving view of human genetic disease transmission","volume":"3","author":"Badano","year":"2002","journal-title":"Nat. Rev. Genet."},{"key":"2019062808325089100_B15","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.cell.2011.02.016","article-title":"Interactome networks and human disease","volume":"144","author":"Vidal","year":"2011","journal-title":"Cell"},{"key":"2019062808325089100_B16","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1038\/nmeth.3289","article-title":"dSysMap: exploring the edgetic role of disease mutations","volume":"12","author":"Mosca","year":"2015","journal-title":"Nat. Methods"},{"key":"2019062808325089100_B17","doi-asserted-by":"crossref","first-page":"1257601","DOI":"10.1126\/science.1257601","article-title":"Disease networks. Uncovering disease-disease relationships through the incomplete interactome","volume":"347","author":"Menche","year":"2015","journal-title":"Science"},{"key":"2019062808325089100_B18","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.2217\/bmm.15.96","article-title":"NETBAGs: a network-based clustering approach with gene signatures for cancer subtyping analysis","volume":"9","author":"Wu","year":"2015","journal-title":"Biomarkers Med."},{"key":"2019062808325089100_B19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pcbi.1006657","article-title":"A data-driven interactome of synergistic genes improves network-based cancer outcome prediction","volume":"15","author":"Allahyar","year":"2019","journal-title":"PLoS Comput. Biol."},{"key":"2019062808325089100_B20","doi-asserted-by":"crossref","first-page":"D900","DOI":"10.1093\/nar\/gkv1068","article-title":"DIDA: a curated and annotated digenic diseases database","volume":"44","author":"Gazzo","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2019062808325089100_B21","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1815601116","article-title":"Predicting disease-causing variant combinations","author":"Papadimitriou","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2019062808325089100_B22","doi-asserted-by":"crossref","first-page":"e140","DOI":"10.1093\/nar\/gkx557","article-title":"Understanding mutational effects in digenic diseases","volume":"45","author":"Gazzo","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2019062808325089100_B23","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.1093\/bioinformatics\/btr330","article-title":"The variant call format and VCFtools","volume":"27","author":"Danecek","year":"2011","journal-title":"Bioinformatics"},{"key":"2019062808325089100_B24","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1038\/nature19057","article-title":"Analysis of protein-coding genetic variation in 60,706 humans","volume":"536","author":"Consortium","year":"2016","journal-title":"Nature"},{"key":"2019062808325089100_B25","first-page":"D754","article-title":"Ensembl 2018","volume":"46","author":"Frankish","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2019062808325089100_B26","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1093\/nar\/gky092","article-title":"UniProt: the universal protein knowledgebase","volume":"46","author":"UniProt\u00a0Consortium","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2019062808325089100_B27","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/humu.22932","article-title":"dbNSFP v3.0: A One-Stop database of functional predictions and annotations for human nonsynonymous and Splice-Site SNVs","volume":"37","author":"Liu","year":"2016","journal-title":"Hum. Mutat."},{"key":"2019062808325089100_B28","doi-asserted-by":"crossref","first-page":"13615","DOI":"10.1073\/pnas.1518646112","article-title":"The human gene damage index as a gene-level approach to prioritizing exome variants","volume":"112","author":"Itan","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2019062808325089100_B29","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1186\/1471-2164-15-256","article-title":"HGCS: an online tool for prioritizing disease-causing gene variants by biological distance","volume":"15","author":"Itan","year":"2014","journal-title":"BMC Genomics"},{"key":"2019062808325089100_B30","first-page":"112","article-title":"Interpreting random forest models using a feature contribution method","volume-title":"Information Reuse and Integration, 2013 14th International Conference on IEEE","author":"Palczewska","year":"2013"},{"key":"2019062808325089100_B31","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nrg1272","article-title":"Network biology: understanding the cell\u2019s functional organization","volume":"5","author":"Barabasi","year":"2004","journal-title":"Nat. Rev. Genet."},{"key":"2019062808325089100_B32","doi-asserted-by":"crossref","first-page":"D485","DOI":"10.1093\/nar\/gku1007","article-title":"ComPPI: a cellular compartment-specific database for protein\u2013protein interaction network analysis","volume":"43","author":"Veres","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"2019062808325089100_B33","doi-asserted-by":"crossref","first-page":"D649","DOI":"10.1093\/nar\/gkx1132","article-title":"The reactome pathway knowledgebase","volume":"46","author":"Fabregat","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2019062808325089100_B34","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.jelectrocard.2019.01.002","article-title":"Sudden death in mild hypertrophic cardiomyopathy with compound DSG2\/DSC2\/MYH6 mutations: revisiting phenotype after genetic assessment in a master runner athlete","volume":"53","author":"Castellana","year":"2019","journal-title":"J. Electrocardiol."},{"key":"2019062808325089100_B35","doi-asserted-by":"crossref","first-page":"1663","DOI":"10.3390\/ijms18081633","article-title":"Allelic complexity in long QT syndrome : a family-case study","volume":"18","author":"Zullo","year":"2017","journal-title":"Int. J. Mol. Sci."}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/nar\/advance-article-pdf\/doi\/10.1093\/nar\/gkz437\/28747452\/gkz437.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/nar\/article-pdf\/47\/W1\/W93\/28879802\/gkz437.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,20]],"date-time":"2019-09-20T11:40:19Z","timestamp":1568979619000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/47\/W1\/W93\/5506854"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,5,31]]},"references-count":35,"journal-issue":{"issue":"W1","published-online":{"date-parts":[[2019,5,31]]},"published-print":{"date-parts":[[2019,7,2]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkz437","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.735854963.793562484","asserted-by":"object"}]},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,7,2]]},"published":{"date-parts":[[2019,5,31]]}}}