학술논문
Phenotypic similarity-based approach for variant prioritization for unsolved rare disease: a preliminary methodological report.
Document Type
Academic Journal
Author
Lagorce D; INSERM, US14 - Orphanet, Plateforme Maladies Rares, 75014, Paris, France. david.lagorce@inserm.fr.; Lebreton E; INSERM, US14 - Orphanet, Plateforme Maladies Rares, 75014, Paris, France.; Matalonga L; CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Baldiri Reixac 4, Barcelona, 08028, Spain.; Hongnat O; INSERM, US14 - Orphanet, Plateforme Maladies Rares, 75014, Paris, France.; Chahdil M; INSERM, US14 - Orphanet, Plateforme Maladies Rares, 75014, Paris, France.; Piscia D; CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Baldiri Reixac 4, Barcelona, 08028, Spain.; Paramonov I; CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Baldiri Reixac 4, Barcelona, 08028, Spain.; Ellwanger K; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.; Köhler S; Ada Health GmbH, Berlin, Germany.; Robinson P; The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA.; Graessner H; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.; Centre for Rare Diseases, University of Tübingen, Tübingen, Germany.; Beltran S; CNAG-CRG, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Baldiri Reixac 4, Barcelona, 08028, Spain.; Lucano C; INSERM, US14 - Orphanet, Plateforme Maladies Rares, 75014, Paris, France.; Hanauer M; INSERM, US14 - Orphanet, Plateforme Maladies Rares, 75014, Paris, France.; Rath A; INSERM, US14 - Orphanet, Plateforme Maladies Rares, 75014, Paris, France.
Source
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 9302235 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5438 (Electronic) Linking ISSN: 10184813 NLM ISO Abbreviation: Eur J Hum Genet Subsets: MEDLINE
Subject
Language
English
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.
(© 2023. The Author(s).)
(© 2023. The Author(s).)