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Title: The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.
Austin Authors: Chatron, Nicolas;Møller, Rikke S;Champaigne, Neena L;Schneider, Amy L ;Kuechler, Alma;Labalme, Audrey;Simonet, Thomas;Baggett, Lauren;Bardel, Claire;Kamsteeg, Erik-Jan;Pfundt, Rolph;Romano, Corrado;Aronsson, Johan;Alberti, Antonino;Vinci, Mirella;Miranda, Maria J;Lacroix, Amy;Marjanovic, Dragan;des Portes, Vincent;Edery, Patrick;Wieczorek, Dagmar;Gardella, Elena;Scheffer, Ingrid E ;Mefford, Heather;Sanlaville, Damien;Carvill, Gemma L;Lesca, Gaetan
Affiliation: Department of Medical Genetics, Lyon University Hospital and GENDEV team CNRS UMR 5292, INSERM U1028, CRNL, and University Claude Bernard Lyon 1, GHE - Lyon, France
Danish Epilepsy Centre, Dianalund, and University of Southern Denmark, Institute for Regional Health research, Odense, Denmark
Greenwood Genetic Center, Greenwood, South Carolina, USA
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Institut für Humangenetik, Universitätsklinikum, and Universität Duisburg-Essen, Essen, Germany
Service de Biostatistique-Bioinformatique, Lyon University Hospital, Lyon and CNRS UMR5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique Santé, Villeurbanne, and University Claude Bernard Lyon 1, Lyon, France
Centre de Biotechnologie Cellulaire, Hospices Civils de Lyon, Lyon, and Nerve-Muscle Interactions Team, Institut NeuroMyoGène CNRS UMR 5310 - INSERM U1217 - Université Claude Bernard Lyon 1, France
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Oasi Research Institute - IRCCS, Troina, Italy
Habiliteringscentrum, Ryhov hospital, Jönköping, Sweden
Department of Pediatrics, Pediatric Neurology, Herlev University Hospital, Copenhagen, Denmark
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, 98195, USA
Centre de référence « Déficiences Intellectuelles de causes rares », HCL, F-69675, Bron ;  ISC, CNRS UMR 5304, F-69677, Bron ; Université de Lyon, F-69008, Lyon, France
Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany
Institut für Humangenetik, Universitätsklinikum Düsseldorf, Düsseldorf, Germany
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia
Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Parkville, Victoria, Australia
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA
Issue Date: 2018
Date: 2018-04-06
Publication information: Annals of neurology 2018; 83(5): 926-934
Abstract: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II-III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n=5) or targeted gene panel (n=4). We performed electroclinical and imaging phenotyping on all patients. The cohort comprised 7 males and 2 females. Mean age at study was 13 years [0.5-21]. Median age at seizure onset was 6 months [2 months to 9 years]. Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on EEG was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug-resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2) and West Syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in one. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in six. The p.Glu590Lys variant affects a highly-conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum which is predominantly generalized epilepsy, with infantile-onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. This article is protected by copyright. All rights reserved.
DOI: 10.1002/ana.25222
ORCID: 0000-0002-2311-2174
Journal: Annals of neurology
PubMed URL: 29630738
Type: Journal Article
Subjects: CUT domain
de novo variant
developmental and epileptic encephalopathy
intellectual disability
myoclonic seizures
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