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. Supplementary Information The online version contains supplementary material available at 10.1186/s13073-023-01214-2.
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Agatha Schlüter, Valentina Vélez-Santamaría, Edgard Verdura et al.. ClinPrior: an algorithm for diagnosis and novel gene discovery by network-based prioritization. Genome Medicine. (2023). https://doi.org/10.1186/s13073-023-01214-2 Agatha Schlüter, Valentina Vélez-Santamaría, Edgard Verdura, Agustí Rodríguez-Palmero, Montserrat Ruiz, Stéphane Fourcade, Laura Planas-Serra, Nathalie Launay, Cristina Guilera, Juan José Martínez, Christian Homedes-Pedret, M. Antonia Albertí-Aguiló, Miren Zulaika, Itxaso Martí, Mónica Troncoso, Miguel Tomás-Vila, Gemma Bullich, M. Asunción García-Pérez, María-Jesús Sobrido-Gómez, Eduardo López-Laso, Carme Fons, Mireia Del Toro, Alfons Macaya, Sergi Beltran, Luis G. Gutiérrez-Solana, Luis A. Pérez-Jurado, Sergio Aguilera-Albesa, Adolfo López de Munain, Carlos Casasnovas, Aurora Pujol, Àngels García-Cazorla, Antonio José Ortiz-Martínez, Carlos Ignacio-Ortez, Cristina Cáceres-Marzal, Eduardo Martínez-Salcedo, Elisabet Mondragón, Estíbaliz Barredo, Ileana Antón Airaldi, Javier Ruiz Martínez, Joaquin A. Fernández Ramos, Juan Francisco Vázquez, Laura Díez-Porras, María Vázquez-Cancela, Mar O’Callaghan, Tamara Pablo Sánchez, Velina Nedkova, Ana Isabel Maraña Pérez
1Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), Hospital Duran i Reynals, Gran Via 199, L’Hospitalet de Llobregat, Barcelona, 08908 Spain 2https://ror.org/01ygm5w19grid.452372.50000 0004 1791 1185Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain 3grid.5841.80000 0004 1937 0247Neurology Department, Neuromuscular Unit, Bellvitge University Hospital, Universitat de Barcelona, Barcelona, Spain 4grid.411438.b0000 0004 1767 6330Pediatric Neurology Unit, Pediatrics Department, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Spain 5grid.440254.30000 0004 1793 6999Neurology Department, Hospital Universitari General de Catalunya, Barcelona, Spain 6grid.432380.eNeuromuscular Area, Group of Neurodegenerative Diseases, Biodonostia Health Research Institute (Biodonostia HRI), San Sebastian, Spain 7grid.418264.d0000 0004 1762 4012Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), ISCIII, Madrid, Spain 8https://ror.org/000xsnr85grid.11480.3c0000 0001 2167 1098Pediatric Neurology Department, Donostia University Hospital, University of the Basque Country (UPV-EHU), San Sebastian, Spain 9grid.443909.30000 0004 0385 4466Pediatric Neurology Department, Central Campus, Hospital Clínico San Borja Arriarán, Universidad de Chile, Santiago, Chile 10https://ror.org/01ar2v535grid.84393.350000 0001 0360 9602Neuropediatrics Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain 11grid.473715.30000 0004 6475 7299Centro Nacional Análisis Genómico (CNAG) - Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Baldiri Reixac 4, Barcelona, Spain 12https://ror.org/01435q086grid.411316.00000 0004 1767 1089Pediatric Neurology Unit, Pediatrics Department, Hospital Universitario Fundación Alcorcón, Madrid, Spain 13grid.488921.eCoruña Institute of Biomedical Research (INIBIC), A Coruña, Spain 14Hospital Clínico Universitario, A Coruña, Spain 15grid.411349.a0000 0004 1771 4667Pediatric Neurology Unit, Pediatrics Department, Reina Sofía University Hospital, Córdoba, Spain 16grid.428865.50000 0004 0445 6160Maimonides Institute For Biomedical Research of Cordoba (IMIBIC), Córdoba, Spain 17grid.410458.c0000 0000 9635 9413Pediatric Neurology Department, Sant Joan de Déu University Hospital, Member of the ERN EpiCARE, Barcelona, Spain 18Sant Joan de Déu Research Institute, (IRSJD), Barcelona, Spain 19https://ror.org/052g8jq94grid.7080.f0000 0001 2296 0625Pediatric Neurology Department, Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain 20grid.430994.30000 0004 1763 0287Pediatric Neurology Research Group, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain 21https://ror.org/04n0g0b29grid.5612.00000 0001 2172 2676Universitat Pompeu Fabra (UPF), Barcelona, Spain 22https://ror.org/021018s57grid.5841.80000 0004 1937 0247Departament de Genètica, Facultat de Biologia, Microbiologia i Estadística, Universitat de Barcelona (UB), Barcelona, 08028 Spain 23grid.411107.20000 0004 1767 5442Pediatric Neurology Department, Children’s University Hospital Niño Jesús, Madrid, Spain 24https://ror.org/042nkmz09grid.20522.370000 0004 1767 9005Genetics Service, Hospital del Mar Research Institute (IMIM), Barcelona, Spain 25https://ror.org/04n0g0b29grid.5612.00000 0001 2172 2676Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain 26Pediatric Neurology Unit, Pediatrics Department, Navarra Health Service, Pamplona, Spain 27https://ror.org/03atdda90grid.428855.6Navarrabiomed, Biomedical Research Center, Pamplona, Spain 28grid.414651.30000 0000 9920 5292Neurology Department, Donostia University Hospital, San Sebastian, Spain 29https://ror.org/0371hy230grid.425902.80000 0000 9601 989XCatalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia Spain 