Journal Article

DZNE-2025-00325

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses.

Laurie, S. ; Steyaert, W. ; de Boer, E. ; Polavarapu, K. ; Schuermans, N. ; Sommer, A. K. ; Demidov, G. ; Ellwanger, K. ; Paramonov, I. ; Thomas, C. ; Aretz, S. ; Baets, J. ; Benetti, E. ; Bullich, G. ; Chinnery, P. F. ; Clayton-Smith, J. ; Cohen, E. ; Danis, D. ; de Sainte Agathe, J.-M. ; Denommé-Pichon, A.-S. ; Diaz-Manera, J. ; Efthymiou, S. ; Faivre, L. ; Fernandez-Callejo, M. ; Freeberg, M. ; Garcia-Pelaez, J. ; Guillot-Noel, L. ; Haack, T. B. ; Hanna, M. ; Hengel, H.DZNE* ; Horvath, R. ; Houlden, H. ; Jackson, A. ; Johansson, L. ; Johari, M. ; Kamsteeg, E.-J. ; Kellner, M.DZNE* ; Kleefstra, T. ; Lacombe, D. ; Lochmüller, H. ; López-Martín, E. ; Macaya, A. ; Marcé-Grau, A. ; Maver, A. ; Morsy, H. ; Muntoni, F. ; Musacchia, F. ; Nelson, I. ; Nigro, V. ; Olimpio, C. ; Oliveira, C. ; Paulasová Schwabová, J. ; Pauly, M. G. ; Peterlin, B. ; Peters, S. ; Pfundt, R. ; Piluso, G. ; Piscia, D. ; Posada, M. ; Reich, S.DZNE* ; Renieri, A. ; Ryba, L. ; Šablauskas, K. ; Savarese, M. ; Schöls, L.DZNE* ; Schütz, L. ; Steinke-Lange, V. ; Stevanin, G. ; Straub, V. ; Sturm, M. ; Swertz, M. A. ; Tartaglia, M. ; Te Paske, I. B. A. W. ; Thompson, R. ; Torella, A. ; Trainor, C. ; Udd, B. ; Van de Vondel, L. ; van de Warrenburg, B. ; van Reeuwijk, J. ; Vandrovcova, J. ; Vitobello, A. ; Vos, J. ; Vyhnálková, E. ; Wijngaard, R. ; Wilke, C.DZNE* ; William, D. ; Xu, J.DZNE* ; Yaldiz, B. ; Zalatnai, L. ; Zurek, B. ; DITF-GENTURIS, S.-R. (Collaboration Author) ; DITF-ITHACA, S.-R. (Collaboration Author) ; DITF-EURO-NMD, S.-R. (Collaboration Author) ; DITF-RND, S.-R. (Collaboration Author) ; consortium, S.-R. (Collaboration Author) ; Brookes, A. J. ; Evangelista, T. ; Gilissen, C. ; Graessner, H. ; Hoogerbrugge, N. ; Ossowski, S. ; Riess, O. ; Schüle, R.DZNE* ; Synofzik, M.DZNE* ; Verloes, A. ; Matalonga, L. ; Brunner, H. G. ; Lohmann, K. ; de Voer, R. M. ; Töpf, A. ; Vissers, L. E. L. M. ; Beltran, S. ; Hoischen, A. ; de Voer, R. M. (Contributor) ; Te Paske, I. B. A. W. (Contributor) ; de Boer, E. (Contributor) ; de Sainte Agathe, J.-M. (Contributor) ; Van de Vondel, L. (Contributor) ; van de Warrenburg, B. (Contributor) ; Vissers, L. E. L. M. (Contributor)

2025
Springer Nature [New York, NY]

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Please use a persistent id in citations: doi: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.

Keyword(s): Humans (MeSH) ; Rare Diseases: genetics (MeSH) ; Rare Diseases: diagnosis (MeSH) ; Europe (MeSH) ; Male (MeSH) ; Genomics: methods (MeSH) ; Female (MeSH) ; Pedigree (MeSH) ; Databases, Genetic (MeSH) ; Computational Biology: methods (MeSH) ; Genome, Human: genetics (MeSH) ; Exome: genetics (MeSH)

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. Clinical Neurogenetics (AG Schöls)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 80 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article (Erratum/Correction) Laurie, S. ; Steyaert, W. ; de Boer, E. ; et al
Publisher Correction: Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses.
Nature medicine 31(8), 2819 - 2820 (2025) [10.1038/s41591-025-03754-z]2025   Files  Fulltext by Pubmed Central BibTeX | EndNote: XML, Text | RIS

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