• Michael Zech, Robert Jech, Sylvia Boesch, Matej Škorvánek, Sandrina Weber, Matias Wagner, Chen Zhao, Angela Jochim, Ján Necpál, Yasemin Dincer, Katharina Vill, Felix Distelmaier, Malgorzata Stoklosa, Martin Krenn, Stephan Grunwald, Tobias Bock-Bierbaum, Anna Fečíková, Petra Havránková, Jan Roth, Iva Příhodová, Miriam Adamovičová, Olga Ulmanová, Karel Bechyně, Pavlína Danhofer, Branislav Veselý, Vladimír Haň, Petra Pavelekova, Zuzana Gdovinová, Tobias Mantel, Tobias Meindl, Alexandra Sitzberger, Sebastian Schröder, Astrid Blaschek, Timo Roser, Michaela V Bonfert, Edda Haberlandt, Barbara Plecko, Birgit Leineweber, Steffen Berweck, Thomas Herberhold, Berthold Langguth, Jana Švantnerová, Michal Minár, Gonzalo Alonso Ramos-Rivera, Monica H Wojcik, Sander Pajusalu, Katrin Õunap, Ulrich A Schatz, Laura Pölsler, Ivan Milenkovic, Franco Laccone, Veronika Pilshofer, Roberto Colombo, Steffi Patzer, Arcangela Iuso, Julia Vera, Monica Troncoso, Fang Fang, Holger Prokisch, Friederike Wilbert, Matthias Eckenweiler, Elisabeth Graf, Dominik S Westphal, Korbinian M Riedhammer, Theresa Brunet, Bader Alhaddad, Riccardo Berutti, Tim M Strom, Martin Hecht, Matthias Baumann, Marc Wolf, Aida Telegrafi, Richard E Person, Francisca Millan Zamora, Lindsay B Henderson, David Weise, Thomas Musacchio, Jens Volkmann, Anna Szuto, Jessica Becker, Kirsten Cremer, Thomas Sycha, Fritz Zimprich, Verena Kraus, Christine Makowski, Pedro Gonzalez-Alegre, Tanya M Bardakjian, Laurie J Ozelius, Annalisa Vetro, Renzo Guerrini, Esther Maier, Ingo Borggraefe, Alice Kuster, Saskia B Wortmann, Annette Hackenberg, Robert Steinfeld, Birgit Assmann, Christian Staufner, Thomas Opladen, Evžen Růžička, Ronald D Cohn, David Dyment, Wendy K Chung, Hartmut Engels, Andres Ceballos-Baumann, Rafal Ploski, Oliver Daumke, Bernhard Haslinger, Volker Mall, Konrad Oexle, and Juliane Winkelmann.
• Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University of Munich, Munich, Germany.
• Lancet Neurol. 2020 Nov 1; 19 (11): 908-918.

BackgroundDystonia 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.MethodsFor 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.FindingsWe 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.InterpretationIn 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.FundingElse 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.Copyright © 2020 Elsevier Ltd. All rights reserved.

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