Integrating Long-Read Nanopore Sequencing for Precision Resolution of Genomic Variants in Dystonia

Sorrentino U. Pavlov M. Mirza-Schreiber N. Brugger M. Brunet T. Tsoma E. Saparov A. Dzinovic I. Harrer P. Stehr A.M. Wagner M. Tilch E. Wallacher B. Alhasan S. Koy A. Di Fonzo A. Kolnikova M. Kusikova K. Havrankova P. Tautanova R. Lösecke S. Eck S. Boesch S. Necpal J. Skorvanek M. Jech R. Prokisch H. Winkelmann J. Oexle K. Graf E. Zech M.
January 2026 John Wiley and Sons Inc

Movement Disorders
2026 #41 Issue 1 70 - 83 pp.

Background: Although many individuals with dystonia present with features indicative of single-gene etiologies, obtaining definitive genetic diagnoses can be challenging. Objective: We assessed the value of nanopore-based long-read sequencing (LRS) in achieving molecular clarification of dystonic syndromes. Methods: From a large dystonia cohort with short-read sequencing (SRS) data, 14 cases with unclear, difficult-to-evaluate, or missing causative variants were recruited. Long-read whole-genome sequencing was performed according to Oxford Nanopore Technologies (ONT) protocols. Results: ONT sequencing produced long-range haplotypes, variant calls inaccessible to short-read technology, as well as methylation data. Phase inference allowed for changes in variant classification, establishing compound heterozygosity of causative variants in four cases. We illustrate an important advantage of LRS compared with SRS in (re)defining the identity of dystonia-causing structural variants and repeat expansions for seven individuals. One patient was found to harbor a novel exonic LINE-1 insertion in SGCE, expanding the genetic mechanism in myoclonus-dystonia. ONT data also provided unexpected insights into apparent mosaic expanded repeats in FMR1 in a subject with isolated focal dystonia. We further showed that LRS outperformed SRS in avoiding erroneous calls resulting from confounding pseudogene sequences and in discovering pathogenic alterations missed by conventional pipeline utilization (three cases). Moreover, simultaneous methylome analysis aided in directing the interpretation of three variants, including a KMT2B variant of uncertain significance that was reclassified as causal by LRS-based episignature profiling. Conclusions: ONT-based LRS uniquely improves analysis of dystonia-associated variations that had not previously been resolved by SRS, implying broad utility for future exploration of the molecular origins of the condition. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

complex structural variants , dystonia , long-range phasing , long-read sequencing , nanopore technology , repeat expansions

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Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich, Germany
Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany
Neurogenetic Systems Analysis Group, Institute of Neurogenomics, Helmholtz Munich, Neuherberg, Germany
Bavarian Genomes Network for Rare Disorders, Munich, Germany
Regional Clinical Center of Neurosurgery and Neurology, Department of Family Medicine and Outpatient Care, Uzhhorod National University, Uzhhorod, Ukraine
Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine Charles University and General University Hospital in Prague, Prague, Czech Republic
Division of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Childrens Hospital, LMU Hospital, Ludwig-Maximilians-Universität, Munich, Germany
Specialist Center for Pediatric Neurology, Neurorehabilitation and Epileptology, Schön Clinic, Vogtareuth, Germany
Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Center for Rare Diseases, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
Foundation IRCCS Ca′ Granda Ospedale Maggiore Policlinico, Neurology Unit, Milan, Italy
Department of Pediatric Neurology, Faculty of Medicine, Comenius University, University Hospital Bratislava and National Institute of Childrens Diseases, Bratislava, Slovakia
Department of Neurosurgery, Medical Centre Hospital of the Presidents Affairs Administration of the Republic of Kazakhstan, Astana, Kazakhstan
Department of Neurology, Medical University of Innsbruck, Innsbruk, Austria
Department of Neurology, Zvolen Hospital, Zvolen, Slovakia
Parkinsonism and Movement Disorders Treatment Center, Zvolen Hospital, Zvolen, Slovakia
Department of Neurology, P. J. Safarik University, Kosice, Slovakia
Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovakia
Deutsches Zentrum Für Kinder- und Jugendgesundheit, Munich, Germany
Deutsches Zentrum Für Psychische Gesundheit, Munich, Germany
Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
Institute for Advanced Study, Technical University of Munich, Garching, Germany

Institute of Human Genetics
Institute of Neurogenomics
Neurogenetic Systems Analysis Group
Bavarian Genomes Network for Rare Disorders
Regional Clinical Center of Neurosurgery and Neurology
Department of Neurology and Center of Clinical Neuroscience
Division of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity
Specialist Center for Pediatric Neurology
Department of Pediatrics
Center for Rare Diseases
Dino Ferrari Center
Foundation IRCCS Ca′ Granda Ospedale Maggiore Policlinico
Department of Pediatric Neurology
Department of Neurosurgery
Department of Neurology
Department of Neurology
Parkinsonism and Movement Disorders Treatment Center
Department of Neurology
Department of Neurology
Deutsches Zentrum Für Kinder- und Jugendgesundheit
Deutsches Zentrum Für Psychische Gesundheit
Munich Cluster for Systems Neurology
Institute for Advanced Study

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