ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization
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...
| Authors: | ; ; ; ; |
|---|---|
| Format: | Article |
| Status: | Published version |
| Publication date: | 2023 |
| Country: | España |
| Institution: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repository: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:10230/58563 |
| Online Access: | http://hdl.handle.net/10230/58563 http://dx.doi.org/10.1186/s13073-023-01214-2 |
| Access Level: | Open access |
| Keyword: | Algorithm Candidate gene Cerebellar ataxia HPOs Hereditary spastic paraplegia Interactome Variant prioritization WES/WGS |
| _version_ | 1878736185560399872 |
|---|---|
| author | Schlüter, Agatha |
| author2 | Bullich, Gemma Beltran, Sergi Pérez Jurado, Luis Alberto Pujol, Aurora, 1968- |
| author2_role | author author author author |
| author_browse | Beltran, Sergi Bullich, Gemma Pujol, Aurora, 1968- Pérez Jurado, Luis Alberto Schlüter, Agatha |
| author_facet | Schlüter, Agatha Bullich, Gemma Beltran, Sergi Pérez Jurado, Luis Alberto Pujol, Aurora, 1968- |
| author_role | author |
| collection | Recercat. Dipósit de la Recerca de Catalunya |
| description | 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_8a851a6bd4e1da322e8d45bc6f4fc3d9 |
| institution | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| instname_str | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:recercat.cat:10230/58563 |
| publishDate | 2023 |
| publishDateSort | 2023 |
| publisher | BioMed Central |
| publisherStr | BioMed Central |
| reponame_str | Recercat. Dipósit de la Recerca de Catalunya |
| spelling | ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization Schlüter, Agatha Bullich, Gemma Beltran, Sergi Pérez Jurado, Luis Alberto Pujol, Aurora, 1968- Algorithm Candidate gene Cerebellar ataxia HPOs Hereditary spastic paraplegia Interactome Variant prioritization WES/WGS 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. BioMed Central http://hdl.handle.net/10230/58563 http://dx.doi.org/10.1186/s13073-023-01214-2 |
| spellingShingle | ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization Schlüter, Agatha Algorithm Candidate gene Cerebellar ataxia HPOs Hereditary spastic paraplegia Interactome Variant prioritization WES/WGS |
| status_str | publishedVersion |
| title | ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization |
| title_full | ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization |
| title_fullStr | ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization |
| title_full_unstemmed | ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization |
| title_short | ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization |
| title_sort | ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization |
| topic | Algorithm Candidate gene Cerebellar ataxia HPOs Hereditary spastic paraplegia Interactome Variant prioritization WES/WGS |
| topic_facet | Algorithm Candidate gene Cerebellar ataxia HPOs Hereditary spastic paraplegia Interactome Variant prioritization WES/WGS |
| url | http://hdl.handle.net/10230/58563 http://dx.doi.org/10.1186/s13073-023-01214-2 |