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<p>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 (<i>n</i> = 67), recently reclassified in ClinVar (<i>n</i> = 187) or reclassified by consensus expert decision within Solve-RD (<i>n</i> = 210). Bespoke bioinformatics analyses identified the remaining 15.9% of causative variants (<i>n</i> = 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.</p>

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Genomic reanalysis of a pan-European rare-disease resource yields new diagnoses

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月17日

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

摘要

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.