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Monogenic variants in dystonia: an exome-wide sequencing study
M. Zech, R. Jech, S. Boesch, M. Škorvánek, S. Weber, M. Wagner, C. Zhao, A. Jochim, J. Necpál, Y. Dincer, K. Vill, F. Distelmaier, M. Stoklosa, M. Krenn, S. Grunwald, T. Bock-Bierbaum, A. Fečíková, P. Havránková, J. Roth, I. Příhodová, M....
Language English Country Great Britain
Document type Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
UM1 HG008900
NHGRI NIH HHS - United States
R01 HG009141
NHGRI NIH HHS - United States
NLK
ProQuest Central
from 2002-05-01 to 2 months ago
Nursing & Allied Health Database (ProQuest)
from 2002-05-01 to 2 months ago
Health & Medicine (ProQuest)
from 2002-05-01 to 2 months ago
Psychology Database (ProQuest)
from 2002-05-01 to 2 months ago
- MeSH
- Child MeSH
- Dystonia diagnosis epidemiology genetics MeSH
- Exome genetics MeSH
- Genetic Variation genetics MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Pedigree MeSH
- Exome Sequencing methods MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Infant, Newborn MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
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. FUNDING: Else 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.
Broad Institute of MIT and Harvard Cambridge MA USA
Child Neurology Service Hospital San Borja Arriarán University of Chile Santiago Chile
Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa ON Canada
Clinic for Pediatrics Krankenhaus Stadt Dornbirn Dornbirn Austria
Crystallography Max Delbrück Center for Molecular Medicine Berlin Germany
Department of Clinical Genetics Tartu University Hospital Tartu Estonia
Department of Clinical Genetics University of Tartu Tartu Estonia
Department of Genetics Yale School of Medicine New Haven CT USA
Department of Medical Genetics Medical University of Warsaw Warsaw Poland
Department of Molecular Genetics University of Toronto Toronto ON Canada
Department of Neonatology Clinical Hospital No 2 Rzeszow Poland
Department of Nephrology Klinikum rechts der Isar Technical University of Munich Munich Germany
Department of Neurology Faculty Hospital Constantine the Philosopher University Nitra Slovakia
Department of Neurology Hospital Písek Pisek Czech Republic
Department of Neurology Massachusetts General Hospital Charlestown MA USA
Department of Neurology Medical University Innsbruck Innsbruck Austria
Department of Neurology Medical University of Vienna Vienna Austria
Department of Neurology Pavol Jozef Šafárik University Košice Slovakia
Department of Neurology University Hospital of Louis Pasteur Košice Slovakia
Department of Neurology University Hospital Würzburg Würzburg Germany
Department of Neurology Zvolen Hospital Zvolen Slovakia
Department of Paediatric Neurology Thomayer Hospital Prague Czech Republic
Department of Paediatrics Hospital for Sick Children and University of Toronto Toronto ON Canada
Department of Paediatrics School of Medicine Technical University of Munich Munich Germany
Department of Pediatric Neurology National Institute of Children's Diseases Bratislava Slovakia
Department of Pediatric Neurology University Children's Hospital Zürich Switzerland
Department of Pediatrics and Department of Medicine Columbia University New York NY USA
Department of Pediatrics Medical University Innsbruck Innsbruck Austria
Department of Psychiatry and Psychotherapy University of Regensburg Regensburg Germany
Dr von Haunersches Kinderspital Ludwig Maximilians Universität München Munich Germany
Fondazione Policlinico Universitario A Gemelli IRCCS Università Cattolica del Sacro Cuore Rome Italy
Institute of Chemistry and Biochemistry Free University of Berlin Berlin Germany
Institute of Human Genetics Medical University Innsbruck Innsbruck Austria
Institute of Human Genetics Technical University of Munich Munich Germany
Institute of Human Genetics University of Bonn and University Hospital Bonn Bonn Germany
Institute of Medical Genetics Medical University of Vienna Vienna Austria
Institute of Neurogenomics Helmholtz Zentrum München Munich Germany
kbo Kinderzentrum München Munich Germany
Klinik für Kinder und Jugendmedizin St Elisabeth und St Barbara Halle Germany
Klinik für Neurologie Asklepios Fachklinikum Stadtroda Stadtroda Germany
Lehrstuhl für Neurogenetik Technical University of Munich Munich Germany
Lehrstuhl für Sozialpädiatrie Technical University of Munich Munich Germany
Ludwig Maximilians Universität München Munich Germany
Munich Cluster for Systems Neurology SyNergy Munich Germany
Neurologische Klinik am Klinikum Kaufbeuren Bezirkskliniken Schwaben Kaufbeuren Germany
Neurologische Klinik Klinikum Stuttgart Stuttgart Germany
Neurologische Klinik Universitätsmedizin Mannheim Mannheim University of Heidelberg Mannheim Germany
Ordensklinikum Linz Barmherzige Schwestern Linz Austria
Schön Klinik München Schwabing Munich Germany
Sozialpädiatrisches Zentrum Klinikum Dritter Orden Munich Germany
Zentrum für Humangenetik und Laboratoriumsdiagnostik Martinsried Germany
References provided by Crossref.org
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- 700 1_
- $a Makowski, Christine $u Department of Paediatrics, School of Medicine, Technical University of Munich, Munich, Germany.
- 700 1_
- $a Gonzalez-Alegre, Pedro $u Department of Neurology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
- 700 1_
- $a Bardakjian, Tanya M $u Department of Neurology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.
- 700 1_
- $a Ozelius, Laurie J $u Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
- 700 1_
- $a Vetro, Annalisa $u Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, Florence, Italy.
- 700 1_
- $a Guerrini, Renzo $u Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, Florence, Italy.
- 700 1_
- $a Maier, Esther $u Dr von Haunersches Kinderspital, Ludwig-Maximilians-Universität München, Munich, Germany.
- 700 1_
- $a Borggraefe, Ingo $u Dr von Haunersches Kinderspital, Ludwig-Maximilians-Universität München, Munich, Germany.
- 700 1_
- $a Kuster, Alice $u Inborn Errors of Metabolism, Pediatric Intensive Care Unit, University Hospital of Nantes, Nantes, France.
- 700 1_
- $a Wortmann, Saskia B $u Institute of Human Genetics, Technical University of Munich, Munich, Germany; University Children's Hospital, Salzburger Landeskliniken and Paracelsus Medical University, Salzburg, Austria; Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children's Hospital, Radboudumc, Nijmegen, Netherlands.
- 700 1_
- $a Hackenberg, Annette $u Department of Pediatric Neurology, University Children's Hospital, Zürich, Switzerland.
- 700 1_
- $a Steinfeld, Robert $u Department of Pediatric Neurology, University Children's Hospital, Zürich, Switzerland.
- 700 1_
- $a Assmann, Birgit $u Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, University Hospital Heidelberg, Heidelberg, Germany.
- 700 1_
- $a Staufner, Christian $u Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, University Hospital Heidelberg, Heidelberg, Germany.
- 700 1_
- $a Opladen, Thomas $u Division of Neuropediatrics and Metabolic Medicine, Department of General Pediatrics, University Hospital Heidelberg, Heidelberg, Germany.
- 700 1_
- $a Růžička, Evžen $u Department of Neurology, Charles University and General University Hospital in Prague, Prague, Czech Republic.
- 700 1_
- $a Cohn, Ronald D $u Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada; Hospital for Sick Children Research Institute, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
- 700 1_
- $a Dyment, David $u Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada.
- 700 1_
- $a Chung, Wendy K $u Department of Pediatrics and Department of Medicine, Columbia University, New York, NY, USA.
- 700 1_
- $a Engels, Hartmut $u Institute of Human Genetics, University of Bonn and University Hospital Bonn, Bonn, Germany.
- 700 1_
- $a Ceballos-Baumann, Andres $u Schön Klinik München Schwabing, Munich, Germany.
- 700 1_
- $a Ploski, Rafal $u Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland.
- 700 1_
- $a Daumke, Oliver $u Crystallography, Max Delbrück Center for Molecular Medicine, Berlin, Germany; Institute of Chemistry and Biochemistry, Free University of Berlin, Berlin, Germany.
- 700 1_
- $a Haslinger, Bernhard $u Klinik und Poliklinik für Neurologie, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
- 700 1_
- $a Mall, Volker $u Lehrstuhl für Sozialpädiatrie, Technical University of Munich, Munich, Germany; kbo-Kinderzentrum München, Munich, Germany.
- 700 1_
- $a Oexle, Konrad $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
- 700 1_
- $a Winkelmann, Juliane $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University of Munich, Munich, Germany; Lehrstuhl für Neurogenetik, Technical University of Munich, Munich, Germany; Munich Cluster for Systems Neurology, SyNergy, Munich, Germany. Electronic address: juliane.winkelmann@tum.de.
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- $w MED00006921 $t Lancet neurology $x 1474-4465 $g Roč. 19, č. 11 (2020), s. 908-918
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