Phenotypic similarity-based approach for variant prioritization for unsolved rare disease: a preliminary methodological report

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• dc.contributor.author Lagorce, David
• dc.contributor.author Lebreton, Emeline
• dc.contributor.author Matalonga, Leslie
• dc.contributor.author Hongnat, Oscar
• dc.contributor.author Chahdil, Maroua
• dc.contributor.author Piscia, Davide
• dc.contributor.author Paramonov, Ida
• dc.contributor.author Ellwanger, Kornelia
• dc.contributor.author Köhler, Sebastian
• dc.contributor.author Robinson, Peter N.
• dc.contributor.author Graessner, Holm
• dc.contributor.author Beltran, Sergi
• dc.contributor.author Lucano, Caterina
• dc.contributor.author Hanauer, Marc
• dc.contributor.author Rath, Ana
• dc.date.accessioned 2024-02-08T07:10:10Z
• dc.date.available 2024-02-08T07:10:10Z
• dc.date.issued 2023
• dc.description Data de publicació electrònica: 06-11-2023
• dc.description.abstract Rare diseases (RD) have a prevalence of not more than 1/2000 persons in the European population, and are characterised by the difficulty experienced in obtaining a correct and timely diagnosis. According to Orphanet, 72.5% of RD have a genetic origin although 35% of them do not yet have an identified causative gene. A significant proportion of patients suspected to have a genetic RD receive an inconclusive exome/genome sequencing. Working towards the International Rare Diseases Research Consortium (IRDiRC)'s goal for 2027 to ensure that all people living with a RD receive a diagnosis within one year of coming to medical attention, the Solve-RD project aims to identify the molecular causes underlying undiagnosed RD. As part of this strategy, we developed a phenotypic similarity-based variant prioritization methodology comparing submitted cases with other submitted cases and with known RD in Orphanet. Three complementary approaches based on phenotypic similarity calculations using the Human Phenotype Ontology (HPO), the Orphanet Rare Diseases Ontology (ORDO) and the HPO-ORDO Ontological Module (HOOM) were developed; genomic data reanalysis was performed by the RD-Connect Genome-Phenome Analysis Platform (GPAP). The methodology was tested in 4 exemplary cases discussed with experts from European Reference Networks. Variants of interest (pathogenic or likely pathogenic) were detected in 8.8% of the 725 cases clustered by similarity calculations. Diagnostic hypotheses were validated in 42.1% of them and needed further exploration in another 10.9%. Based on the promising results, we are devising an automated standardized phenotypic-based re-analysis pipeline to be applied to the entire unsolved cases cohort.
• dc.description.sponsorship The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. This study makes use of data shared/provided through RD-Connect, which received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 305444.
• dc.format.mimetype application/pdf
• dc.identifier.citation Lagorce D, Lebreton E, Matalonga L, Hongnat O, Chahdil M, Piscia D, Paramonov I, Ellwanger K, Köhler S, Robinson P, Graessner H, Beltran S, Lucano C, Hanauer M, Rath A. Phenotypic similarity-based approach for variant prioritization for unsolved rare disease: a preliminary methodological report. Eur J Hum Genet. 2023 Nov 6. DOI: 10.1038/s41431-023-01486-7
• dc.identifier.doi http://dx.doi.org/10.1038/s41431-023-01486-7
• dc.identifier.issn 1018-4813
• dc.identifier.uri http://hdl.handle.net/10230/58995
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Eur J Hum Genet. 2023 Nov 6
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/779257
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305444
• dc.rights © The Author(s) 2023. 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 Genome informatics
• dc.subject.keyword Spinocerebellar ataxia
• dc.title Phenotypic similarity-based approach for variant prioritization for unsolved rare disease: a preliminary methodological report
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion