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Monogenic variants in dystonia: an exome-wide sequencing study

Item Type:Article
Title:Monogenic variants in dystonia: an exome-wide sequencing study
Creators Name:Zech, M. and Jech, R. and Boesch, S. and Škorvánek, M. and Weber, S. and Wagner, M. and Zhao, C. and Jochim, A. and Necpál, J. and Dincer, Y. and Vill, K. and Distelmaier, F. and Stoklosa, M. and Krenn, M. and Grunwald, S. and Bock-Bierbaum, T. and Fečíková, A. and Havránková, P. and Roth, J. and Příhodová, I. and Adamovičová, M. and Ulmanová, O. and Bechyně, K. and Danhofer, P. and Veselý, B. and Haň, V. and Pavelekova, P. and Gdovinová, Z. and Mantel, T. and Meindl, T. and Sitzberger, A. and Schröder, S. and Blaschek, A. and Roser, T. and Bonfert, M.V. and Haberlandt, E. and Plecko, B. and Leineweber, B. and Berweck, S. and Herberhold, T. and Langguth, B. and Švantnerová, J. and Minár, M. and Ramos-Rivera, G.A. and Wojcik, M.H. and Pajusalu, S. and Õunap, K. and Schatz, U.A. and Pölsler, L. and Milenkovic, I. and Laccone, F. and Pilshofer, V. and Colombo, R. and Patzer, S. and Iuso, A. and Vera, J. and Troncoso, M. and Fang, F. and Prokisch, H. and Wilbert, F. and Eckenweiler, M. and Graf, E. and Westphal, D.S. and Riedhammer, K.M. and Brunet, T. and Alhaddad, B. and Berutti, R. and Strom, T.M. and Hecht, M. and Baumann, M. and Wolf, M. and Telegrafi, A. and Person, R.E. and Zamora, F.M. and Henderson, L.B. and Weise, D. and Musacchio, T. and Volkmann, J. and Szuto, A. and Becker, J. and Cremer, K. and Sycha, T. and Zimprich, F. and Kraus, V. and Makowski, C. and Gonzalez-Alegre, P. and Bardakjian, T.M. and Ozelius, L.J. and Vetro, A. and Guerrini, R. and Maier, E. and Borggraefe, I. and Kuster, A. and Wortmann, S.B. and Hackenberg, A. and Steinfeld, R. and Assmann, B. and Staufner, C. and Opladen, T. and Růžička, E. and Cohn, R.D. and Dyment, D. and Chung, W.K. and Engels, H. and Ceballos-Baumann, A. and Ploski, R. and Daumke, O. and Haslinger, B. and Mall, V. and Oexle, K. and Winkelmann, J.
Abstract: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.
Keywords:Dystonia, Exome, Genetic Variation, Pedigree, Whole Exome Sequencing
Source:Lancet Neurology
Page Range:908-918
Date:November 2020
Additional Information:Copyright © 2020 Elsevier Ltd. All rights reserved.
Official Publication:https://doi.org/10.1016/S1474-4422(20)30312-4
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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