20.500.12556/DiRROS-24134 Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses 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. rare diseases identification interpretation genetic diagnosis genomic variants true false true Angleški jezik Ni določen Neznano 2025-11-17 13:14:10 2025-11-17 13:14:10 2025-11-18 03:43:32 0000-00-00 00:00:00 2025 0 0 Nasl. z nasl. zaslona; Opis vira z dne 19. 6. 2025; str. 478–489 Vol. 31 Feb. 2025 0000-00-00 Zaloznikova Objavljeno apc 0000-00-00 0000-00-00 0000-00-00 61:575 1546-170X 10.1038/s41591-024-03420-w 239892227 RAZ_Laurie_Steven_2025.pdf RAZ_Laurie_Steven_2025.pdf 1 C738E209A6CB2FCFF76842279B769329 75a04d439a878c2b68cef15b3387eea4d40f75dca4fd7fa31c8d798b5a95f12a 193e8798-c3af-11f0-94a7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=35913 https://www.nature.com/articles/s41591-024-03420-w 0 2cd04048-c3af-11f0-94a7-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=35914 Univerzitetni klinični center Ljubljana 0 0 0