Moreno-Ruiz, NereaGenomics England Research ConsortiumLao Grueso, Oscar, 1976-Aróstegui Gorospe, Juan IgnacioLaayouni, Hafid, 1968-Casals López, Ferran2023-03-022023-03-022022Moreno-Ruiz N; Genomics England Research Consortium; Lao O, Aróstegui JI, Laayouni H, Casals F. Assessing the digenic model in rare disorders using population sequencing data. Eur J Hum Genet. 2022 Dec;30(12):1439-43. DOI: 10.1038/s41431-022-01191-x1018-4813http://hdl.handle.net/10230/56006An important fraction of patients with rare disorders remains with no clear genetic diagnostic, even after whole-exome or whole-genome sequencing, posing a difficulty in giving adequate treatment and genetic counseling. The analysis of genomic data in rare disorders mostly considers the presence of single gene variants in coding regions that follow a concrete monogenic mode of inheritance. A digenic inheritance, with variants in two functionally-related genes in the same individual, is a plausible alternative that might explain the genetic basis of the disease in some cases. In this case, digenic disease combinations should be absent or underrepresented in healthy individuals. We develop a framework to evaluate the significance of digenic combinations and test its statistical power in different scenarios. We suggest that this approach will be relevant with the advent of new sequencing efforts including hundreds of thousands of samples.application/pdfeng© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41431-022-01191-xDiseasesGenetic interactionPopulation geneticsinfo:eu-repo/semantics/openAccess