Assessing the digenic model in rare disorders using population sequencing data

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  • dc.contributor.author Moreno-Ruiz, Nerea
  • dc.contributor.author Genomics England Research Consortium
  • dc.contributor.author Lao Grueso, Oscar, 1976-
  • dc.contributor.author Aróstegui Gorospe, Juan Ignacio
  • dc.contributor.author Laayouni, Hafid, 1968-
  • dc.contributor.author Casals López, Ferran
  • dc.date.accessioned 2023-03-02T07:05:27Z
  • dc.date.available 2023-03-02T07:05:27Z
  • dc.date.issued 2022
  • dc.description.abstract An 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.
  • dc.description.sponsorship This study was funded by grants RTI2018-096824-B-C22 (FC), PID2021-125106OB-C32 (FC), RTI2018-096824-B-C21 (JIA) and PID2021-125106OB-C31 (JIA) funded by MCIN/ AEI /10.13039/501100011033/ and FEDER Una manera de hacer Europa; Direcció General de Recerca- Generalitat de Catalunya (2017SGR-702) (FC); and CERCA Programme/Generalitat de Catalunya (JIA). NMR was supported by grant 2021 FI_B_00296 from Agència de Gestió d’Ajuts Universitaris i de Recerca, Generalitat de Catalunya. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Moreno-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-x
  • dc.identifier.doi http://dx.doi.org/10.1038/s41431-022-01191-x
  • dc.identifier.issn 1018-4813
  • dc.identifier.uri http://hdl.handle.net/10230/56006
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Eur J Hum Genet. 2022 Dec;30(12):1439-43
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-096824-B-C22
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-125106OB-C32
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-096824-B-C21
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-125106OB-C31
  • dc.rights © 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/
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Diseases
  • dc.subject.keyword Genetic interaction
  • dc.subject.keyword Population genetics
  • dc.title Assessing the digenic model in rare disorders using population sequencing data
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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