Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses.
LACOMBE, Didier
Hôpital Pellegrin
Service de génétique médicale
Chercheur indépendant
Université de Bordeaux [UB]
Centre Hospitalier Universitaire de Bordeaux [CHU Bordeaux]
CHU de Bordeaux Pellegrin [Bordeaux]
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
< Réduire
Hôpital Pellegrin
Service de génétique médicale
Chercheur indépendant
Université de Bordeaux [UB]
Centre Hospitalier Universitaire de Bordeaux [CHU Bordeaux]
CHU de Bordeaux Pellegrin [Bordeaux]
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]
Langue
EN
Article de revue
Ce document a été publié dans
Nature Medicine. 2025-01-17, vol. 31, n° 2, p. 478-489
Résumé en anglais
Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium ...Lire la suite >
Genetic diagnosis of rare diseases requires accurate identification and interpretation of genomic variants. Clinical and molecular scientists from 37 expert centers across Europe created the Solve-Rare Diseases Consortium (Solve-RD) resource, encompassing clinical, pedigree and genomic rare-disease data (94.5% exomes, 5.5% genomes), and performed systematic reanalysis for 6,447 individuals (3,592 male, 2,855 female) with previously undiagnosed rare diseases from 6,004 families. We established a collaborative, two-level expert review infrastructure that allowed a genetic diagnosis in 506 (8.4%) families. Of 552 disease-causing variants identified, 464 (84.1%) were single-nucleotide variants or short insertions/deletions. These variants were either located in recently published novel disease genes (n = 67), recently reclassified in ClinVar (n = 187) or reclassified by consensus expert decision within Solve-RD (n = 210). Bespoke bioinformatics analyses identified the remaining 15.9% of causative variants (n = 88). Ad hoc expert review, parallel to the systematic reanalysis, diagnosed 249 (4.1%) additional families for an overall diagnostic yield of 12.6%. The infrastructure and collaborative networks set up by Solve-RD can serve as a blueprint for future further scalable international efforts. The resource is open to the global rare-disease community, allowing phenotype, variant and gene queries, as well as genome-wide discoveries.< Réduire
Mots clés en anglais
Humans
Rare Diseases
Europe
Genomics
Male
Female
Pedigree
Databases
Genetic
Genetic Testing
Computational Biology
Polymorphism
Single Nucleotide
Genetic Predisposition to Disease
Unités de recherche