Title Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses /
Authors Laurie, Steven ; Steyaert, Wouter ; de Boer, Elke ; Polavarapu, Kiran ; Schuermans, Nika ; Sommer, Anna K ; Demidov, German ; Ellwanger, Kornelia ; Paramonov, Ida ; Thomas, Coline ; Aretz, Stefan ; Baets, Jonathan ; Benetti, Elisa ; Bullich, Gemma ; Chinnery, Patrick F ; Clayton-Smith, Jill ; Cohen, Enzo ; Danis, Daniel ; de Sainte Agathe, Jean-Madeleine ; Denomme-Pichon, Anne-Sophie ; Diaz-Manera, Jordi ; Efthymiou, Stephanie ; Faivre, Laurence ; Fernandez-Callejo, Marcos ; Freeberg, Mallory ; Garcia-Pelaez, Jose ; Guillot-Noel, Lena ; Haack, Tobias B ; Hanna, Mike ; Hengel, Holger ; Horvath, Rita ; Houlden, Henry ; Jackson, Adam ; Johansson, Lennart ; Johari, Mridul ; Kamsteeg, Erik-Jan ; Kellner, Melanie ; Kleefstra, Tjitske ; Lacombe, Didier ; Lochmueller, Hanns ; Lopez-Martin, Estrella ; Macaya, Alfons ; Marce-Grau, Anna ; Maver, Ales ; Morsy, Heba ; Muntoni, Francesco ; Musacchia, Francesco ; Nelson, Isabelle ; Nigro, Vincenzo ; Olimpio, Catarina ; Oliveira, Carla ; Schwabova, Jaroslava Paulasova ; Pauly, Martje G ; Peterlin, Borut ; Peters, Sophia ; Pfundt, Rolph ; Piluso, Giulio ; Piscia, Davide ; Posada, Manuel ; Reich, Selina ; Renieri, Alessandra ; Ryba, Lukas ; Šablauskas, Karolis ; Savarese, Marco ; Schoels, Ludger ; Schuetz, Leon ; Steinke-Lange, Verena ; Stevanin, Giovanni ; Straub, Volker ; Sturm, Marc ; Swertz, Morris A ; Tartaglia, Marco ; te Paske, Iris B. A. W ; Thompson, Rachel ; Torella, Annalaura ; Trainor, Christina ; Udd, Bjarne ; Van de Vondel, Liedewei ; van de Warrenburg, Bart ; van Reeuwijk, Jeroen ; Vandrovcova, Jana ; Vitobello, Antonio ; Vos, Janet ; Vyhnalkova, Emilie ; Wijngaard, Robin ; Wilke, Carlo ; William, Doreen ; Xu, Jishu ; Yaldiz, Burcu ; Zalatnai, Luca ; Zurek, Birte ; Brookes, Anthony J ; Evangelista, Teresinha ; Gilissen, Christian ; Graessner, Holm ; Hoogerbrugge, Nicoline ; Ossowski, Stephan ; Riess, Olaf ; Schuele, Rebecca ; Synofzik, Matthis ; Verloes, Alain ; Matalonga, Leslie ; Brunner, Han G ; Lohmann, Katja ; de Voer, Richarda M ; Topf, Ana ; Vissers, Lisenka E. L. M ; Beltran, Sergi ; Hoischen, Alexander
DOI 10.1038/s41591-024-03420-w
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Is Part of Nature medicine.. Berlin : Nature Portfolio. 2025, vol. 31, iss. 2, p. 478-489.. ISSN 1078-8956. eISSN 1546-170X
Abstract [eng] 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.
Published Berlin : Nature Portfolio
Type Journal article
Language English
Publication date 2025
CC license CC license description