Phenotypic similarity-based approach for variant prioritization for unsolved rare disease: a preliminary methodological report.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
06 Nov 2023
06 Nov 2023
Historique:
received:
17
05
2023
accepted:
05
10
2023
revised:
13
09
2023
medline:
6
11
2023
pubmed:
6
11
2023
entrez:
5
11
2023
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 37926714
doi: 10.1038/s41431-023-01486-7
pii: 10.1038/s41431-023-01486-7
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Organisme : European Commission (EC)
ID : 779257
Informations de copyright
© 2023. The Author(s).
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