Zech, Michael and Jech, Robert and Boesch, Sylvia and Skorvanek, Matej and Weber, Sandrina and Wagner, Matias and Zhao, Chen and Jochim, Angela and Necpal, Jan and Dincer, Yasemin and Vill, Katharina and Disteimaier, Felix and Stoklosa, Malgorzata and Krenn, Martin and Grunwald, Stephan and Bock-Bierbaum, Tobias and Fecikova, Anna and Havrankova, Petra and Roth, Jan and Prihodova, Iva and Adamovicova, Miriam and Ulmanova, Olga and Bechyne, Karel and Danhofer, Pavlina and Vesely, Branislav and Han, Vladimir and Pavelekova, Petra and Gdovinova, Zuzana and Mantel, Tobias and Meindl, Tobias and Sitzberger, Alexandra and Schroeder, Sebastian and Blaschek, Astrid and Roser, Timo and Bonfert, Michaefa and Haberlandt, Edda and Plecko, Barbara and Leineweber, Birgit and Berweck, Steffen and Herberhold, Thomas and Langguth, Berthold and Svantnerova, Jana and Minar, Michal and Ramos-Rivera, Gonzalo Alonso and Wojcik, Monica H. and Pajusalu, Sander and Ounap, Katrin and Schatz, Ulrich A. and Poelsler, Laura and Milenkovic, Ivan and Laccone, Franco and Pilhofer, Veronika and Colombo, Roberto and Patzer, Steffi and Iuso, Arcangela and Vera, Julia and Troncoso, Monica and Fang, Fang and Prokisch, Holger and Wilbert, Friederike and Eckenweiler, Matthias and Graf, Elisabeth and Westphal, Dominik S. and Riedhammer, Korbinian M. and Brunet, Theresa and Alhaddad, Bader and Berutti, Riccardo and Strom, Tim M. and Hecht, Martin and Baumann, Matthias and Wolf, Marc and Telegrafi, Aida and Person, Richard E. and Zamora, Francisca Milian and Henderson, Lindsay B. and Weise, David and Musacchio, Thomas and Volkmann, Jens and Szuto, Anna and Becker, Jessica and Cremer, Kirsten and Sycha, Thomas and Zimprich, Fritz and Kraus, Verena and Makowski, Christine and Gonzalez-Alegre, Pedro and Bardakjian, Tanya M. and Ozelius, Laurie J. and Vetro, Annafisa and Guerrini, Renzo and Maier, Esther and Borggraefe, Ingo and Kuster, Alice and Wortmann, Saskia B. and Hackenberg, Annette and Steinfeld, Robert and Assmann, Birgit and Staufner, Christian and Opladen, Thomas and Ruzicka, Evzen and Cohn, Ronald D. and Dyment, David and Chung, Wendy K. and Engels, Hartmut and Ceballos-Baumann, Andres and Ploski, Rafai and Daumke, Ofiver and Haslinger, Bernhard and Mall, Volker and Oexle, Konrad and Winkelmann, Juliane (2020) Monogenic variants in dystonia: an exome-wide sequencing study. LANCET NEUROLOGY, 19 (11). pp. 908-918. ISSN 1474-4422, 1474-4465
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CLASSIFICATION; DISORDER; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Psychiatrie und Psychotherapie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Mar 2021 10:44 |
| Last Modified: | 08 Mar 2021 10:44 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43477 |
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