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.

Brain and Mind Research Institute University of Ottawa Ottawa Ontario Canada

Center for Hereditary Tumor Syndromes University Hospital Bonn Bonn Germany

Center for Medical Genetics Ghent University Hospital Ghent Belgium

Center of Excellence for Neuropsychiatry Vincent van Gogh Institute for Psychiatry Venray the Netherlands

Centre de Recherche en Myologie Sorbonne Université Inserm Institut de Myologie Paris France

Centre for Rare Diseases University of Tübingen Tübingen Germany

Centre of Hereditary Ataxia Department of Neurology Charles University Prague 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Centre of Reference for Rare Diseases Development Disorders and Malformation Syndromes Dijon University Hospital Dijon France

Centro Nacional de Análisis Genómico Barcelona Spain

Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa Ontario Canada

Clinical Institute of Genomic Medicine University Medical Centre Ljubljana Ljubljana Slovenia

Departament de Genètica Microbiologia i Estadística Facultat de Biologia Universitat de Barcelona Barcelona Spain

Department of Biology and Medical Genetics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Biomolecular Medicine Faculty of Medicine and Health Sciences Ghent University Ghent Belgium

Department of Clinical Genetics Erasmus MC Rotterdam the Netherlands

Department of Clinical Genetics Maastricht University Medical Centre and GROW School for Development and Oncology University of Maastricht Maastricht the Netherlands

Department of Clinical Neurosciences University of Cambridge Cambridge UK

Department of Genetics and Genome Biology University of Leicester Leicester UK

Department of Genetics Assistance Publique Hôpitaux de Paris Sorbonne Université Pitié Salpêtrière University Hospital Paris France

Department of Genetics Genomics Coordination Center University Medical Center Groningen University of Groningen Groningen the Netherlands

Department of Human Genetics Medical Research Institute Alexandria University Alexandria Egypt

Department of Human Genetics Radboud University Medical Center Nijmegen the Netherlands

Department of Internal Medicine and Radboud Center for Infectious Diseases Radboud University Medical Center Nijmegen the Netherlands

Department of Neurodegeneration Hertie Institute for Clinical Brain Research University of Tübingen Tübingen Germany

Department of Neurology Radboud University Medical Center Nijmegen the Netherlands

Department of Neurology University Hospital Schleswig Holstein Lübeck Germany

Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology London UK

Department of Neuropediatrics and Muscle Disorders Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Dept of Genetics Assistance Publique Hôpitaux de Paris Université de Paris Robert DEBRE University Hospital Paris France

Dipartimento di Medicina di Precisione Università degli Studi della Campania Luigi Vanvitelli Naples Italy

Division of Evolution Infection and Genomics School of Biological Sciences Faculty of Biology Medicine and Health University of Manchester Manchester UK

Division of Neurology Department of Medicine The Ottawa Hospital Ottawa Ontario Canada

Donders Institute for Brain Cognition and Behaviour Radboud University Medical Center Nijmegen the Netherlands

Dubowitz Neuromuscular Centre UCL Great Ormond Street Hospital London UK

East Anglian Medical Genetics Service Cambridge University Hospitals NHS Foundation Trust Cambridge UK

European Bioinformatics Institute European Molecular Biology Laboratory Cambridge UK

Faculty of Medicine University of Porto Porto Portugal

Folkhälsan Research Centre and Medicum University of Helsinki Helsinki Finland

Functional Unit for Diagnostic Innovation in Rare Diseases Dijon Bourgogne University Hospital Dijon France

Genetica Medica Azienda Ospedaliero Universitaria Senese Siena Italy

Genetics Department Dijon University Hospital Dijon France

German Center for Neurodegenerative Diseases Tübingen Germany

GIMI institute Dijon University Hospital Dijon France

INSERM UMR 1141 NeuroDiderot Hôpital Robert DEBRE Paris France

Institut du Cerveau Sorbonne University Paris France

Institute of Clinical Genetics University Hospital Carl Gustav Carus Technical University Dresden Dresden Germany

Institute of Data Science and Digital Technologies Vilnius University Vilnius Lithuania

Institute of Human Genetics Medical Faculty University of Bonn Bonn Germany

Institute of Medical Genetics and Applied Genomics University of Tübingen Tübingen Germany

Institute of Neurogenetics University of Lübeck Lübeck Germany

Institute of Rare Diseases Research Spanish Undiagnosed Rare Diseases Cases Program Instituto de Salud Carlos 3 Madrid Spain

Institute of Systems Motor Science University of Lübeck Lübeck Germany

Instituto de Investigação e Inovação em Saúde Universidade do Porto Porto Portugal

IPATIMUP Institute of Molecular Pathology and Immunology of the University of Porto Porto Portugal

Jackson Laboratory for Genomic Medicine Farmington CT USA

John Walton Muscular Dystrophy Research Centre Translational and Clinical Research Institute Newcastle University and Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne UK

Laboratory of Neuromuscular Pathology Institute Born Bunge University of Antwerp Antwerp Belgium

Manchester Centre for Genomic Medicine St Mary's Hospital Manchester University Hospitals NHS Foundation Trust Health Innovation Manchester Manchester UK

Med Biotech Hub and Competence Center Department of Medical Biotechnologies University of Siena Siena Italy

Medical Genetics University of Siena Siena Italy

Medical Research Council Mitochondrial Biology Unit University of Cambridge Cambridge UK

Medizinische Klinik und Poliklinik 4 Campus Innenstadt Klinikum der Universität München Munich Germany

MGZ Medical Genetics Center Munich Germany

Molecular Genetics and Functional Genomics Ospedale Pediatrico Bambino Gesù IRCCS Rome Italy

MRC Centre for Neuromuscular Diseases and National Hospital for Neurology and Neurosurgery UCL Queen Square Institute of Neurology London UK

MRGM Maladies Rares Génétique et Métabolisme INSERM U1211 Université de Bordeaux Bordeaux France

National Center for Tumor Diseases Dresden Germany

Neuromuscular Reference Centre Department of Neurology Antwerp University Hospital Antwerp Belgium

NGS Competence Center Tübingen University of Tübingen Tübingen Germany

NIHR Great Ormond Street Hospital Biomedical Research Centre London UK

Pediatric Neurology Research Group Vall d'Hebron Research Institute Universitat Autònoma de Barcelona Barcelona Spain

Peripheral Neuropathy Research Group University of Antwerp Antwerp Belgium

Program for Undiagnosed Rare Diseases Ghent University Hospital Ghent Belgium

Radboud Institute for Medical Innovation Nijmegen the Netherlands

Service de Génétique Médicale Centre Hospitalier Universitaire de Bordeaux Bordeaux France

Tampere Neuromuscular Center Tampere Finland

Telethon Institute of Genetics and Medicine Pozzuoli Italy

Translational Neurosciences Faculty of Medicine and Health Sciences University of Antwerp Antwerp Belgium

Universitat de Barcelona Barcelona Spain

University of Burgundy Dijon France

University of Burgundy Franche Comté Dijon France

Vasa Central Hospital Vaasa Finland

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