Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses
Authors: Steven Laurie, Wouter Steyaert, Elke de Boer, Kiran Polavarapu, Nika Schuermans, Anna K. Sommer, German Demidov, Kornelia Ellwanger, Ida Paramonov, Coline Thomas, Stefan Aretz, Jonathan Baets, Elisa Benetti, Gemma Bullich, Patrick F. Chinnery, Jill Clayton-Smith, Enzo Cohen, Daniel Danis, Jean-Madeleine de Sainte Agathe, Anne-Sophie Denommé-Pichon, Jordi Diaz-Manera, Stephanie Efthymiou, Laurence Faivre, Marcos Fernandez-Callejo, Mallory Freeberg, José Garcia-Pelaez, Lena Guillot-Noel, Tobias B. Haack, Mike Hanna, Holger Hengel, Rita Horvath, Henry Houlden, Adam Jackson, Lennart Johansson, Mridul Johari, Erik-Jan Kamsteeg, Melanie Kellner, Tjitske Kleefstra, Didier Lacombe, Hanns Lochmüller, Estrella López-Martín, Alfons Macaya, Anna Marcé-Grau, Aleš Maver, Heba Morsy, Francesco Muntoni, Francesco Musacchia, Isabelle Nelson, Vincenzo Nigro, Catarina Olimpio, Carla Oliveira, Jaroslava Paulasová Schwabová, Martje G. Pauly, Borut Peterlin, Sophia Peters, Rolph Pfundt, Giulio Piluso, Davide Piscia, Manuel Posada, Selina Reich, Alessandra Renieri, Lukas Ryba, Karolis Šablauskas, Marco Savarese, Ludger Schöls, Leon Schütz, Verena Steinke-Lange, Giovanni Stevanin, Volker Straub, Marc Sturm, Morris A. Swertz, Marco Tartaglia, Iris B. A. W. te Paske, Rachel Thompson, Annalaura Torella, Christina Trainor, Bjarne Udd, Liedewei Van de Vondel, Bart van de Warrenburg, Jeroen van Reeuwijk, Jana Vandrovcova, Antonio Vitobello, Janet Vos, Emílie Vyhnálková, Robin Wijngaard, Carlo Wilke, Doreen William, Jishu Xu, Burcu Yaldiz, Luca Zalatnai, Birte Zurek, Richarda M. de Voer, Iris B. A. W. te Paske, Elke de Boer, Jean-Madeleine de Sainte Agathe, Liedewei Van de Vondel, Bart van de Warrenburg, Lisenka E. L. M. Vissers, Anthony J. Brookes, Teresinha Evangelista, Christian Gilissen, Holm Graessner, Nicoline Hoogerbrugge, Stephan Ossowski, Olaf Riess, Rebecca Schüle, Matthis Synofzik, Alain Verloes, Leslie Matalonga, Han G. Brunner, Katja Lohmann, Richarda M. de Voer, Ana Töpf, Lisenka E.L.M. Vissers, Sergi Beltran, Alexander Hoischen
Journal: Nature Medicine (2025)

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.