Document Type
Article
Publication Date
2-1-2025
Publication Title
Nature medicine
Keywords
JGM, Humans, Rare Diseases, Europe, Male, Genomics, Female, Pedigree, Databases, Genetic, Computational Biology, Genome, Human, Exome
JAX Source
Nat Med. 2025;31(2):478-89.
Volume
31
Issue
2
First Page
478
Last Page
489
ISSN
1546-170X
PMID
39825153
DOI
https://doi.org/10.1038/s41591-024-03420-w
Abstract
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.
Recommended Citation
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Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses. Nat Med. 2025;31(2):478-89.