Combined genomics and proteomics unveils elusive variants and vast aetiologic heterogeneity in dystonia

Zech M. Dzinovic I. Skorvanek M. Harrer P. Necpal J. Kopajtich R. Kittke V. Tilch E. Zhao C. Tsoma E. Sorrentino U. Indelicato E. Stehr A. Saparov A. Abela L. Adamovicova M. Afenjar A. Assmann B. Baloghova J. Baumann M. Berutti R. Brezna Z. Brugger M. Brunet T. Cogne B. Colangelo I. Conboy E. Distelmaier F. Eckenweiler M. Garavaglia B. Geerlof A. Graf E. Hackenberg A. Harvanova D. Haslinger B. Havrankova P. Hoffmann G.F. Janzarik W.G. Keren B. Kolnikova M. Kolokotronis K. Kosutzka Z. Koy A. Krenn M. Krygier M. Kusikova K. Maier O. Meitinger T. Mertes C. Milenkovic I. Monfrini E. Santos Dias Mourao A. Musacchio T. Nizon M. Ostrozovicova M. Pavlov M. Prihodova I. Rektorova I. Romito L.M. Rybanska B. Sadr-Nabavi A. Schwenger S. Shoeibi A. Sitzberger A. Smirnov D. Svantnerova J. Tautanova R. Toelle S.P. Ulmanova O. Vetrini F. Vill K. Wagner M. Weise D. Zorzi G. Di Fonzo A. Oexle K. Berweck S. Mall V. Boesch S. Schormair B. Prokisch H. Jech R. Winkelmann J.
1 August 2025 Oxford University Press

Brain
2025 #148 Issue 8 2827 - 2846 pp.

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.

dystonia , genomics , multi-omics , proteomics , transcriptomics , whole-genome sequencing

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Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany
Institute of Neurogenomics, Helmholtz Zentrum München, Munich, 85764, Germany
Institute for Advanced Study, Technical University of Munich, Garching, 85748, Germany
Bavarian Genomes Network for Rare Disorders, Munich, 81675, Germany
Department of Neurology, P.J. Safarik University, Kosice, 4001, Slovakia
Department of Neurology, University Hospital of L. Pasteur, Kosice, 4001, Slovakia
Department of Neurology, Zvolen Hospital, Zvolen, 96001, Slovakia
Parkinsonism and Movement Disorders Treatment Center, Zvolen Hospital, Zvolen, 96001, Slovakia
Department of Family Medicine and Outpatient Care, Regional Clinical Center of Neurosurgery and Neurology, Uzhhorod National University, Uzhhorod, 88000, Ukraine
Department of Womens and Childrens Health, Clinical Genetics Unit, University of Padova, Padua, 35128, Italy
Department of Neurology, Center for Rare Movement Disorders Innsbruck, Medical University of Innsbruck, Innsbruck, 6020, Austria
Department of Pediatric Neurology, University Childrens Hospital Zürich, University of Zürich, Zurich, 8008, Switzerland
Department of Paediatric Neurology, Thomayer University Hospital, Prague, 12108, Czech Republic
Clinical Genetics Unit, Reference Center for Cerebellar Malformations and Congenital Diseases, Armand-Trousseau Hospital, APHP, Sorbonne University, Paris, 75013, France
Center for Pediatric and Adolescent Medicine, Clinic i University Hospital Heidelberg, Heidelberg University, Heidelberg, 69120, Germany
Faculty of Medicine, Department of Dermatovenerology, P. J. Safarik University, Kosice, 4001, Slovakia
Department of Dermatovenerology, University Hospital of L. Pasteur, Kosice, 4001, Slovakia
Division of Pediatric Neurology, Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, 6020, Austria
Center for Advanced Studies, Research and Development in Sardinia, NGS Bioinformatics, Pula, 09010, Italy
Department of Obstetrics and Gynecology, Klinikum Rechts der Isar, Technical University of Munich, Munich, 81675, Germany
Div. of Pediat. Neurol. and Devmtl. Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Childrens Hospital, LMU Hospital, Ludwig-Maximilians-Universität, Munich, 80337, Germany
Nantes Université, CHU de Nantes, CNRS, INSERM, LInstitut du Thorax, Nantes, 44000, France
Nantes Université, CHU de Nantes, Service de Génétique Médicale, Nantes, 44000, France
Medical Genetics and Neurogenetics Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, 20126, Italy
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, 46202, IN, United States
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
Faculty of Medicine, Department of Neuropediatrics and Muscle Disorders, University Medical Center, University of Freiburg, Freiburg, 79110, Germany
Institute of Structural Biology, Helmholtz Center Munich, Munich, 85764, Germany
Faculty of Medicine, Associated Tissue Bank, P. J. Safarik University and L. Pasteur University Hospital in Kosice, Kosice, 4001, Slovakia
Department of Neurology, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany
Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine Charles University and General University Hospital in Prague, Prague, 12108, Czech Republic
Department of Genetics, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, 75013, France
Faculty of Medicine, Department of Pediatric Neurology, Comenius University, University Hospital Bratislava and National Institute of Childrens Diseases, Bratislava, 83340, Slovakia
Institute of Medical Genetics, University of Zurich, Zurich, 8952, Switzerland
Faculty of Medicine, Second Department of Neurology, Comenius University, University Hospital Bratislava, Bratislava, 83340, Slovakia
Faculty of Medicine and University Hospital Cologne, Department of Pediatrics, University of Cologne, Cologne, 50937, Germany
Faculty of Medicine and University Hospital Cologne, Center for Rare Diseases, University of Cologne, Cologne, 50937, Germany
Department of Neurology, Medical University of Vienna, Vienna, 1090, Austria
Comprehensive Center for Clinical Neurosciences & Mental Health, Medical University of Vienna, Vienna, 1090, Austria
Department of Developmental Neurology, Medical University of Gdansk, Gdansk, 80210, Poland
Division of Child Neurology, Department of Pediatrics, Childrens Hospital, St. Gallen, 9000, Switzerland
School of Computation, Information and Technology, Technical University of Munich, Garching, 85748, Germany
Munich Data Science Institute, Technical University of Munich, Garching, 85748, Germany
Department of Pathophysiology and Transplantation, Dino Ferrari Center, Neuroscience Section, University of Milan, Milan, 20122, Italy
Foundation IRCCS Ca Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, 20122, Italy
Department of Neurology, University Hospital of Würzburg, Wurzburg, 97080, Germany
Center for Rare Diseases, University Hospital of Würzburg, Wurzburg, 97080, Germany
Brain and Mind Research Program, CEITEC, Masaryk University, Brno, 62500, Czech Republic
First Department of Neurology, St. Annes University Hospital and Faculty of Medicine, Masaryk University, Brno, 62500, Czech Republic
Parkinson and Movement Disorders Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, 20126, Italy
Faculty of Medicine, Department of Medical Genetics, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran
Medical Genetics Research Center, 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
Academic Center for Education, Culture and Research (ACECR)-Khorasan Razavi, Mashhad, 9177948564, Iran
Kbo-Kinderzentrum München, Munich, 81377, Germany
Department of Neurosurgery, Medical Centre Hospital of the Presidents Affairs Administration of the Republic of Kazakhstan, Astana, E495, Kazakhstan
Department of Neurology, Asklepios Fachklinikum Stadtroda, Stadtroda, 07646, Germany
Department of Neurology, University of Leipzig, Leipzig, 04103, Germany
Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, 20126, Italy
Specialist Center for Pediatric Neurology, Neurorehabilitation and Epileptology, Schön Clinic, Vogtareuth, 83569, Germany
Social Pediatrics, Technical University of Munich, Munich, 80333, Germany
DZKJ, Deutsches Zentrum für Kinder- und Jugendgesundheit, Munich, 80333, Germany
DZPG, Deutsches Zentrum für Psychische Gesundheit, Munich, 80333, Germany
Munich Cluster for Systems Neurology, SyNergy, Munich, 81377, Germany

Institute of Human Genetics
Institute of Neurogenomics
Institute for Advanced Study
Bavarian Genomes Network for Rare Disorders
Department of Neurology
Department of Neurology
Department of Neurology
Parkinsonism and Movement Disorders Treatment Center
Department of Family Medicine and Outpatient Care
Department of Womens and Childrens Health
Department of Neurology
Department of Pediatric Neurology
Department of Paediatric Neurology
Clinical Genetics Unit
Center for Pediatric and Adolescent Medicine
Faculty of Medicine
Department of Dermatovenerology
Division of Pediatric Neurology
Center for Advanced Studies
Department of Obstetrics and Gynecology
Div. of Pediat. Neurol. and Devmtl. Medicine and LMU Center for Children with Medical Complexity
Nantes Université
Nantes Université
Medical Genetics and Neurogenetics Unit
Department of Medical and Molecular Genetics
Department of General Pediatrics
Department of General Pediatrics
Faculty of Medicine
Institute of Structural Biology
Faculty of Medicine
Department of Neurology
Department of Neurology and Center of Clinical Neuroscience
Department of Genetics
Faculty of Medicine
Institute of Medical Genetics
Faculty of Medicine
Faculty of Medicine and University Hospital Cologne
Faculty of Medicine and University Hospital Cologne
Department of Neurology
Comprehensive Center for Clinical Neurosciences & Mental Health
Department of Developmental Neurology
Division of Child Neurology
School of Computation
Munich Data Science Institute
Department of Pathophysiology and Transplantation
Foundation IRCCS Ca Granda Ospedale Maggiore Policlinico
Department of Neurology
Center for Rare Diseases
Brain and Mind Research Program
First Department of Neurology
Parkinson and Movement Disorders Unit
Faculty of Medicine
Medical Genetics Research Center
Faculty of Medicine
Academic Center for Education
Kbo-Kinderzentrum München
Department of Neurosurgery
Department of Neurology
Department of Neurology
Department of Pediatric Neuroscience
Specialist Center for Pediatric Neurology
Social Pediatrics
DZKJ
DZPG
Munich Cluster for Systems Neurology

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