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Zech, M. ; Jech, R.* ; Boesch, S.* ; Škorvánek, M.* ; Weber, S. ; Wagner, M. ; Zhao, C. ; Jochim, A.* ; Necpál, J.* ; Dincer, Y.* ; Vill, K.* ; Disteimaier, F.* ; Stoklosa, M.* ; Krenn, M.* ; Grunwald, S.* ; Bock-Bierbaum, T.* ; Fečíková, A.* ; Havránková, P.* ; Roth, J.* ; Příhodová, I.* ; Adamovičová, M.* ; Ulmanová, O.* ; Bechyně, K.* ; Danhofer, P.* ; Veselý, B.* ; Han, V.* ; Pavelekova, P.* ; Gdovinova, Z.* ; Mantel, T.* ; Meindl, T.* ; Sitzberger, A.* ; Schroeder, S.* ; Blaschek, A.* ; Roser, T.* ; Bonfert, M.* ; Haberlandt, E.* ; Plecko, B.* ; Leineweber, B.* ; Berweck, S.* ; Herberhold, T.* ; Langguth, B.* ; Švantnerová, J.* ; Minár, M.* ; Ramos-Rivera, G.A.* ; Wojcik, M.H.* ; Pajusalu, S.* ; Ounap, K.* ; Schatz, U.A.* ; Poelsler, L.* ; Milenkovic, I.* ; Laccone, F.* ; Pilhofer, V.* ; Colombo, R.* ; Patzer, S.* ; Iuso, A. ; Vera, J.* ; Troncoso, M.* ; Fang, F.* ; Prokisch, H. ; Wilbert, F.* ; Eckenweiler, M.* ; Graf, E.* ; Westphal, D.S.* ; Riedhammer, K.M.* ; Brunet, T.* ; Alhaddad, B.* ; Berutti, R.* ; Strom, T.M.* ; Hecht, M.* ; Baumann, M.* ; Wolf, M.* ; Telegrafi, A.* ; Person, R.E.* ; Zamora, F.M.* ; Henderson, L.B.* ; Weise, D.* ; Musacchio, T.* ; Volkmann, J.* ; Szuto, A.* ; Becker, J.* ; Cremer, K.* ; Sycha, T.* ; Zimprich, F.* ; Kraus, V.* ; Makowski, C.* ; Gonzalez-Alegre, P.* ; Bardakjian, T.M.* ; Ozelius, L.J.* ; Vetro, A.* ; Guerrini, R.* ; Maier, E.* ; Borggraefe, I.* ; Kuster, A.* ; Wortmann, S.B.* ; Hackenberg, A.* ; Steinfeld, R.* ; Assmann, B.* ; Staufner, C.* ; Opladen, T.* ; Ruzicka, E.* ; Cohn, R.D.* ; Dyment, D.* ; Chung, W.K.* ; Engels, H.* ; Ceballos-Baumann, A.* ; Ploski, R.* ; Daumke, O.* ; Haslinger, B.* ; Mall, V.* ; Oexle, K. ; Winkelmann, J.

Monogenic variants in dystonia: An exome-wide sequencing study.

Lancet Neurol. 19, 908-918 (2020)
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Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Classification; Disorder
ISSN (print) / ISBN 1474-4422
e-ISSN 1474-4422
Quellenangaben Volume: 19, Issue: 11, Pages: 908-918 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Ste 800, 230 Park Ave, New York, Ny 10169 Usa
Reviewing status
Grants Slovak Research and Grant Agency
Slovak Grant and Development Agency
European Joint Programme on Rare Diseases
Czech Ministry of Education
Charles University, Prague, Czech Republic
Medizinische Universitat Innsbruck, Innsbruck, Austria
Helmholtz Zentrum Munchen, Munich, Germany
Technische Universitat Munchen, Munich, Germany
Physician Scientists for Groundbreaking Projects at Helmholtz Zentrum Munchen, Munich, Germany
German Research Foundation
Elterninitiative Kinderkrebsklinik (Dusseldorf)
National Heart, Lung and Blood Institute
National Eye Institute
National Human Genome Research Institute
Estonian Research Council
Estonian Research Council
Jeffry Barbara Picower Foundation
Simons Foundation Autism Research Initiative
German Bundesministerium fur Bildung und Forschung through the Personalised Medicine project Personalised Mitochondrial Medicine
Else Kroner-Fresenius-Stiftung