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(Hospital Duran i Reynals (Hospitalet del Llobregat)) (Hospital Duran i Reynals (Hospitalet del Llobregat)) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Hospital Duran i Reynals (Hospitalet del Llobregat)) (Hospital Duran i Reynals (Hospitalet del Llobregat)) (Hospital Duran i Reynals (Hospitalet del Llobregat)) (Hospital Duran i Reynals (Hospitalet del Llobregat)) (Hospital Duran i Reynals (Hospitalet del Llobregat)) (Hospital Universitario de Donostia (Sant Sebastià, País Basc)) (Centro Nacional Análisis Genómico (Barcelona)) (Hospital Universitari Vall d'Hebron) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (Universitat de Barcelona) (Hospital Infantil Universitario Niño Jesús (Madrid)) (Universitat Pompeu Fabra) (Servicio Navarro de Salud) (Hospital Universitari de Bellvitge) (Institució Catalana de Recerca i Estudis Avançats)
| Date: | 2023 |
| Abstract: | 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. 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). 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. 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. The online version contains supplementary material available at 10. 1186/s13073-023-01214-2. |
| Grants: | Generalitat de Catalunya SLT002/16/00174 Fundació la Marató de TV3 202006-30 Fundació la Marató de TV3 504/C/2020 Ministerio de Economía y Competitividad CPII16/00016 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Algorithm ; WES/WGS ; HPOs ; Variant prioritization ; Interactome ; Hereditary spastic paraplegia ; Cerebellar ataxia ; Candidate gene |
| Published in: | Genome medicine, Vol. 15 (september 2023) , ISSN 1756-994X |
