BACKGROUND: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. METHODS: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. FINDINGS: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. INTERPRETATION: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations. FUNDING: Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

2nd Department of Neurology Faculty of Medicine Comenius University University Hospital Bratislava Bratislava Slovakia

Child Neurology Service Hospital San Borja Arriarán University of Chile Santiago Chile

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

Clinic for Pediatrics Krankenhaus Stadt Dornbirn Dornbirn Austria

Crystallography Max Delbrück Center for Molecular Medicine Berlin Germany; Institute of Chemistry and Biochemistry Free University of Berlin Berlin Germany

Department of Child Neurology Faculty of Medicine of Masaryk University Brno and University Hospital Brno Czech Republic

Department of Clinical Genetics Tartu University Hospital Tartu Estonia; Department of Clinical Genetics University of Tartu Tartu Estonia

Department of Clinical Genetics Tartu University Hospital Tartu Estonia; Department of Clinical Genetics University of Tartu Tartu Estonia; Department of Genetics Yale School of Medicine New Haven CT USA

Department of General Pediatrics Neonatology and Pediatric Cardiology University Children's Hospital Heinrich Heine University Düsseldorf Germany

Department of Medical Genetics Medical University of Warsaw Warsaw Poland

Department of Neonatology Clinical Hospital No 2 Rzeszow Poland

Department of Neurology Charles University and General University Hospital Prague Prague Czech Republic

Department of Neurology Faculty Hospital Constantine the Philosopher University Nitra Slovakia

Department of Neurology Hospital Písek Pisek Czech Republic

Department of Neurology Massachusetts General Hospital Charlestown MA USA

Department of Neurology Medical University Innsbruck Innsbruck Austria

Department of Neurology Medical University of Vienna Vienna Austria

Department of Neurology National Center for Children's Health Beijing Children's Hospital and Capital Medical University Beijing China

Department of Neurology Pavol Jozef Šafárik University Košice Slovakia; Department of Neurology University Hospital of Louis Pasteur Košice Slovakia

Department of Neurology Perelman School of Medicine The University of Pennsylvania Philadelphia PA USA

Department of Neurology University Hospital Würzburg Würzburg Germany

Department of Neurology Zvolen Hospital Zvolen Slovakia

Department of Neuropediatrics and Muscle Disorders University Medical Center University of Freiburg Freiburg im Breisgau Germany

Department of Paediatric Neurology Thomayer Hospital Prague Czech Republic

Department of Paediatrics Hospital for Sick Children and University of Toronto Toronto ON Canada; Hospital for Sick Children Research Institute Hospital for Sick Children and University of Toronto Toronto ON Canada; Department of Molecular Genetics University of Toronto Toronto ON Canada

Department of Paediatrics School of Medicine Technical University of Munich Munich Germany

Department of Pediatric Neurology National Institute of Children's Diseases Bratislava Slovakia

Department of Pediatric Neurology University Children's Hospital Zürich Switzerland

Department of Pediatrics and Adolescent Medicine Division of General Pediatrics Medical University of Graz Graz Austria

Department of Pediatrics and Department of Medicine Columbia University New York NY USA

Department of Pediatrics Medical University Innsbruck Innsbruck Austria

Department of Psychiatry and Psychotherapy University of Regensburg Regensburg Germany

Division of Clinical and Metabolic Genetics Hospital for Sick Children and University of Toronto Toronto ON Canada; Department of Paediatrics Hospital for Sick Children and University of Toronto Toronto ON Canada

Division of Neuropediatrics and Metabolic Medicine Department of General Pediatrics University Hospital Heidelberg Heidelberg Germany

Divisions of Newborn Medicine and Genetics and Genomics Department of Pediatrics Boston Children's Hospital Boston MA USA; Broad Institute of MIT and Harvard Cambridge MA USA

Dr von Haunersches Kinderspital Ludwig Maximilians Universität München Munich Germany

Fondazione Policlinico Universitario A Gemelli IRCCS Università Cattolica del Sacro Cuore Rome Italy

GeneDx Gaithersburg MD USA

Hospital for Neuropediatrics and Neurological Rehabilitation Centre of Epilepsy for Children and Adolescents Schoen Klinik Vogtareuth Vogtareuth Germany

Inborn Errors of Metabolism Pediatric Intensive Care Unit University Hospital of Nantes Nantes France

Institute of Human Genetics Medical University Innsbruck Innsbruck Austria

Institute of Human Genetics Technical University of Munich Munich Germany

Institute of Human Genetics Technical University of Munich Munich Germany; Department of Nephrology Klinikum rechts der Isar Technical University of Munich Munich Germany

Institute of Human Genetics Technical University of Munich Munich Germany; Department of Neurology Medical University of Vienna Vienna Austria

Institute of Human Genetics Technical University of Munich Munich Germany; Institute of Human Genetics Medical University Innsbruck Innsbruck Austria

Institute of Human Genetics Technical University of Munich Munich Germany; University Children's Hospital Salzburger Landeskliniken and Paracelsus Medical University Salzburg Austria; Radboud Center for Mitochondrial Medicine Department of Pediatrics Amalia Children's Hospital Radboudumc Nijmegen Netherlands

Institute of Human Genetics University of Bonn and University Hospital Bonn Bonn Germany

Institute of Medical Genetics Medical University of Vienna Vienna Austria

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany; Institute of Human Genetics Technical University of Munich Munich Germany

Institute of Neurogenomics Helmholtz Zentrum München Munich Germany; Institute of Human Genetics Technical University of Munich Munich Germany; Lehrstuhl für Neurogenetik Technical University of Munich Munich Germany; Munich Cluster for Systems Neurology SyNergy Munich Germany

Klinik für Kinder und Jugendmedizin St Elisabeth und St Barbara Halle Germany

Klinik für Neurologie Asklepios Fachklinikum Stadtroda Stadtroda Germany

Klinik und Poliklinik für Neurologie Klinikum rechts der Isar Technical University of Munich Munich Germany

Lehrstuhl für Sozialpädiatrie Technical University of Munich Munich Germany; kbo Kinderzentrum München Munich Germany

Lehrstuhl für Sozialpädiatrie Technical University of Munich Munich Germany; Zentrum für Humangenetik und Laboratoriumsdiagnostik Martinsried Germany

Ludwig Maximilians Universität München Munich Germany; Hospital for Neuropediatrics and Neurological Rehabilitation Centre of Epilepsy for Children and Adolescents Schoen Klinik Vogtareuth Vogtareuth Germany

Neurologische Klinik am Klinikum Kaufbeuren Bezirkskliniken Schwaben Kaufbeuren Germany

Neurologische Klinik Klinikum Stuttgart Stuttgart Germany; Neurologische Klinik Universitätsmedizin Mannheim Mannheim University of Heidelberg Mannheim Germany

Ordensklinikum Linz Barmherzige Schwestern Linz Austria

Pediatric Neurology Neurogenetics and Neurobiology Unit and Laboratories Meyer Children's Hospital University of Florence Florence Italy

Schön Klinik München Schwabing Munich Germany

Sozialpädiatrisches Zentrum Klinikum Dritter Orden Munich Germany

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