ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization

Mostra el registre complet Registre parcial de l'ítem

• dc.contributor.author Schlüter, Agatha
• dc.contributor.author Bullich, Gemma
• dc.contributor.author Beltran, Sergi
• dc.contributor.author Pérez Jurado, Luis Alberto
• dc.contributor.author Pujol, Aurora, 1968-
• dc.date.accessioned 2023-12-18T07:05:25Z
• dc.date.available 2023-12-18T07:05:25Z
• dc.date.issued 2023
• dc.description.abstract Background: Whole-exome sequencing (WES) and whole-genome sequencing (WGS) have become indispensable tools to solve rare Mendelian genetic conditions. Nevertheless, there is still an urgent need for sensitive, fast algorithms to maximise WES/WGS diagnostic yield in rare disease patients. Most tools devoted to this aim take advantage of patient phenotype information for prioritization of genomic data, although are often limited by incomplete gene-phenotype knowledge stored in biomedical databases and a lack of proper benchmarking on real-world patient cohorts. Methods: We developed ClinPrior, a novel method for the analysis of WES/WGS data that ranks candidate causal variants based on the patient's standardized phenotypic features (in Human Phenotype Ontology (HPO) terms). The algorithm propagates the data through an interactome network-based prioritization approach. This algorithm was thoroughly benchmarked using a synthetic patient cohort and was subsequently tested on a heterogeneous prospective, real-world series of 135 families affected by hereditary spastic paraplegia (HSP) and/or cerebellar ataxia (CA). Results: ClinPrior successfully identified causative variants achieving a final positive diagnostic yield of 70% in our real-world cohort. This includes 10 novel candidate genes not previously associated with disease, 7 of which were functionally validated within this project. We used the knowledge generated by ClinPrior to create a specific interactome for HSP/CA disorders thus enabling future diagnoses as well as the discovery of novel disease genes. Conclusions: ClinPrior is an algorithm that uses standardized phenotype information and interactome data to improve clinical genomic diagnosis. It helps in identifying atypical cases and efficiently predicts novel disease-causing genes. This leads to increasing diagnostic yield, shortening of the diagnostic Odysseys and advancing our understanding of human illnesses.
• dc.format.mimetype application/pdf
• dc.identifier.citation Schlüter A, Vélez-Santamaría V, Verdura E, Rodríguez-Palmero A, Ruiz M, Fourcade S, et al. ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization. Genome Med. 2023 Sep 7;15(1):68. DOI: 10.1186/s13073-023-01214-2
• dc.identifier.doi http://dx.doi.org/10.1186/s13073-023-01214-2
• dc.identifier.issn 1756-994X
• dc.identifier.uri http://hdl.handle.net/10230/58563
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Genome Med. 2023 Sep 7;15(1):68
• 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Algorithm
• dc.subject.keyword Candidate gene
• dc.subject.keyword Cerebellar ataxia
• dc.subject.keyword HPOs
• dc.subject.keyword Hereditary spastic paraplegia
• dc.subject.keyword Interactome
• dc.subject.keyword Variant prioritization
• dc.subject.keyword WES/WGS
• dc.title ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion