Dystonia is a rare disease trait for which large-scale genomic investigations are still underrepresented. Genetic heterogeneity among patients with unexplained dystonia warrants interrogation of entire genome sequences, but this has not yet been systematically evaluated. To significantly enhance our understanding of the genetic contribution to dystonia, we (re)analysed 2874 whole-exome sequencing (WES), 564 whole-genome sequencing (WGS), as well as 80 fibroblast-derived proteomics datasets, representing the output of high-throughput analyses in 1990 patients and 973 unaffected relatives from 1877 families. Recruitment and precision-phenotyping procedures were driven by long-term collaborations of international experts with access to overlooked populations. By exploring WES data, we found that continuous scaling of sample sizes resulted in steady gains in the number of associated disease genes without plateauing. On average, every second diagnosis involved a gene not previously implicated in our cohort. Second-line WGS focused on a subcohort of undiagnosed individuals with high likelihood of having monogenic forms of dystonia, comprising large proportions of patients with early onset (81.3%), generalized symptom distribution (50.8%) and/or coexisting features (68.9%). We undertook extensive searches for variants in nuclear and mitochondrial genomes to uncover 38 (ultra)rare diagnostic-grade findings in 37 of 305 index patients (12.1%), many of which had remained undetected due to methodological inferiority of WES or pipeline limitations. WGS-identified elusive variations included alterations in exons poorly covered by WES, RNA-gene variants, mitochondrial-DNA mutations, small copy-number variants, complex rearranged genome structure and short tandem repeats. For improved variant interpretation in WGS-inconclusive cases, we employed systematic integration of quantitative proteomics. This aided in verifying diagnoses related to technically challenging variants and in upgrading a variant of uncertain significance (3 of 70 WGS-inconclusive index patients, 4.3%). Further, unsupervised proteomic outlier analysis supplemented with transcriptome sequencing revealed pathological gene underexpression induced by transcript disruptions in three more index patients with underlying (deep) intronic variants (3/70, 4.3%), highlighting the potential for targeted antisense-oligonucleotide therapy development. Finally, trio-WGS prioritized a de novo missense change in the candidate PRMT1, encoding a histone methyltransferase. Data-sharing strategies supported the discovery of three distinct PRMT1 de novo variants in four phenotypically similar patients, associated with loss-of-function effects in in vitro assays. This work underscores the importance of continually expanding sequencing cohorts to characterize the extensive spectrum of gene aberrations in dystonia. We show that a pool of unresolved cases is amenable to WGS and complementary multi-omic studies, directing advanced aetiopathological concepts and future diagnostic-practice workflows for dystonia.

1st Department of Neurology St Anne's University Hospital and Faculty of Medicine Masaryk University Brno 62500 Czech Republic

Academic Center for Education Culture and Research Khorasan Razavi Mashhad 9177948564 Iran

Bavarian Genomes Network for Rare Disorders Munich 81675 Germany

Brain and Mind Research Program CEITEC Masaryk University Brno 62500 Czech Republic

Center for Advanced Studies Research and Development in Sardinia NGS Bioinformatics Pula 09010 Italy

Center for Pediatric and Adolescent Medicine Clinic 1 University Hospital Heidelberg Heidelberg University Heidelberg 69120 Germany

Center for Rare Diseases University Hospital of Würzburg Wurzburg 97080 Germany

Chair of Social Pediatrics Technical University of Munich Munich 80333 Germany

Clinical Genetics Unit Reference Center for Cerebellar Malformations and Congenital Diseases Armand Trousseau Hospital APHP Sorbonne University Paris 75013 France

Comprehensive Center for Clinical Neurosciences and Mental Health Medical University of Vienna Vienna 1090 Austria

Department of Dermatovenerology University Hospital of L Pasteur Kosice 4001 Slovakia

Department of Developmental Neurology Medical University of Gdansk Gdansk 80210 Poland

Department of Family Medicine and Outpatient Care Regional Clinical Center of Neurosurgery and Neurology Uzhhorod National University Uzhhorod 88000 Ukraine

Department of General Pediatrics Neonatology and Pediatric Cardiology Medical Faculty and University Hospital Düsseldorf Heinrich Heine University Düsseldorf 40225 Germany

Department of General Pediatrics West German Center for Child and Adolescent Health Düsseldorf 40225 Germany

Department of Genetics Pitié Salpêtrière Hospital APHP Sorbonne University Paris 75013 France

Department of Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN 46202 USA

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Prague 12108 Czech Republic

Department of Neurology Asklepios Fachklinikum Stadtroda Stadtroda 07646 Germany

Department of Neurology Center for Rare Movement Disorders Innsbruck Medical University of Innsbruck Innsbruck 6020 Austria

Department of Neurology Klinikum rechts der Isar School of Medicine and Health Technical University of Munich Munich 81675 Germany

Department of Neurology Medical University of Vienna Vienna 1090 Austria

Department of Neurology P J Safarik University Kosice 4001 Slovakia

Department of Neurology University Hospital of L Pasteur Kosice 4001 Slovakia

Department of Neurology University Hospital of Würzburg Wurzburg 97080 Germany

Department of Neurology University of Leipzig Leipzig 04103 Germany

Department of Neurology Zvolen Hospital Zvolen 96001 Slovakia

Department of Neurosurgery Medical Centre Hospital of the President's Affairs Administration of the Republic of Kazakhstan Astana E495 Kazakhstan

Department of Obstetrics and Gynecology Klinikum Rechts der Isar Technical University of Munich Munich 81675 Germany

Department of Paediatric Neurology Thomayer University Hospital Prague 12108 Czech Republic

Department of Pathophysiology and Transplantation Dino Ferrari Center Neuroscience Section University of Milan Milan 20122 Italy

Department of Pediatric Neurology University Children's Hospital Zürich University of Zürich Zurich 8008 Switzerland

Department of Pediatric Neuroscience Fondazione IRCCS Istituto Neurologico Carlo Besta Milan 20126 Italy

Department of Women's and Children's Health Clinical Genetics Unit University of Padova Padua 35128 Italy

Division of Child Neurology Department of Pediatrics Children's Hospital St Gallen 9000 Switzerland

Division of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity Dr von Hauner Children's Hospital LMU Hospital Ludwig Maximilians Universität Munich 80337 Germany

Division of Pediatric Neurology Department of Pediatrics 1 Medical University of Innsbruck Innsbruck 6020 Austria

DZKJ Deutsches Zentrum Für Kinder und Jugendgesundheit Munich 80333 Germany

DZPG Deutsches Zentrum Für Psychische Gesundheit Munich 80333 Germany

Faculty of Medicine 2nd Department of Neurology Comenius University University Hospital Bratislava Bratislava 83340 Slovakia

Faculty of Medicine and University Hospital Cologne Center for Rare Diseases University of Cologne Cologne 50937 Germany

Faculty of Medicine and University Hospital Cologne Department of Pediatrics University of Cologne Cologne 50937 Germany

Faculty of Medicine Associated Tissue Bank P J Safarik University and L Pasteur University Hospital in Kosice Kosice 4001 Slovakia

Faculty of Medicine Department of Dermatovenerology P J Safarik University Kosice 4001 Slovakia

Faculty of Medicine Department of Medical Genetics Mashhad University of Medical Sciences Mashhad 9177948564 Iran

Faculty of Medicine Department of Neurology Mashhad University of Medical Sciences Qaem Medical Center Mashhad 9177948564 Iran

Faculty of Medicine Department of Neuropediatrics and Muscle Disorders University Medical Center University of Freiburg Freiburg 79110 Germany

Faculty of Medicine Department of Pediatric Neurology Comenius University University Hospital Bratislava and National Institute of Children's Diseases Bratislava 83340 Slovakia

Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico Neurology Unit Milan 20122 Italy

Institute for Advanced Study Technical University of Munich Garching 85748 Germany

Institute of Human Genetics School of Medicine and Health Technical University of Munich Munich 81675 Germany

Institute of Medical Genetics University of Zurich Zurich 8952 Switzerland

Institute of Neurogenomics Helmholtz Zentrum München Munich 85764 Germany

Institute of Structural Biology Helmholtz Center Munich Munich 85764 Germany

kbo Kinderzentrum München Munich 81377 Germany

Medical Genetics and Neurogenetics Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan 20126 Italy

Medical Genetics Research Center Mashhad University of Medical Sciences Mashhad 9177948564 Iran

Munich Cluster for Systems Neurology SyNergy Munich 81377 Germany

Munich Data Science Institute Technical University of Munich Garching 85748 Germany

Nantes Université CHU de Nantes CNRS INSERM l'institut du thorax Nantes 44000 France

Nantes Université CHU de Nantes Service de Génétique médicale Nantes 44000 France

Parkinson and Movement Disorders Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan 20126 Italy

Parkinsonism and Movement Disorders Treatment Center Zvolen Hospital Zvolen 96001 Slovakia

School of Computation Information and Technology Technical University of Munich Garching 85748 Germany

Specialist Center for Pediatric Neurology Neurorehabilitation and Epileptology Schön Clinic Vogtareuth 83569 Germany

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Expanding the Allelic and Clinical Heterogeneity of Movement Disorders Linked to Defects of Mitochondrial Adenosine Triphosphate Synthase