article · Nature Medicine
A collaborative initiative across thirty-seven specialist centres compiled clinical, pedigree and genomic information covering 6,447 individuals from 6,004 families affected by previously undiagnosed rare conditions. By deploying a systematic genomic reanalysis process paired with a two-level expert review framework, a definitive genetic diagnosis was achieved for 506 families. Most identified disease-causing variants were single-nucleotide variants or short insertions and deletions, resolved through novel disease genes, updated public classifications or expert consensus. Dedicated bioinformatics analyses uncovered the remaining causative variants. When combined with parallel ad hoc reviews, the overall diagnostic yield reached 12.6 per cent. The resulting open-access infrastructure provides a scalable model enabling global researchers and clinicians to query phenotypes, variants and genes.
Patients with rare diseases frequently endure prolonged searches for a medical explanation. This work demonstrates that periodically re-evaluating existing genomic data using updated scientific knowledge and collective expert review can provide answers for undiagnosed patients without new testing, showing how shared data platforms and improved bioinformatics interpretation directly expand diagnostic success.
The two-tier expert review model and bespoke bioinformatics workflows offer an applied, tested framework for diagnostic laboratories, clinical genetics centres and healthcare software developers. While designed as an open research and clinical resource rather than a commercial product, the methodology can be adopted by commercial genetic testing providers to enhance automated reanalysis pipelines and variant reclassification services.
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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.
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DOI: 10.1038/s41591-024-03420-w
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