The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

Nicolas Chatron; Rikke S. Møller; Neena L. Champaigne; Amy L. Schneider; Alma Kuechler; Audrey Labalme; Thomas Simonet; Lauren Baggett; Claire Bardel; Erik‐Jan Kamsteeg; Rolph Pfundt; Corrado Romano; Johan Aronsson; Antonino Alberti; Mirella Vinci; Maria J. Miranda; Amy Lacroix; Dragan Marjanovic; Vincent Des Portes; Patrick Edery; Dagmar Wieczorek; Elena Gardella; Ingrid E. Scheffer; Heather Mefford; Damien Sanlaville; Gemma L. Carvill; Gaetan Lesca

doi:10.1002/ana.25222

journal article Apr 30, 2018

The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

Rikke S. Møller Neena L. Champaigne Amy L. Schneider Alma Kuechler Audrey Labalme Thomas Simonet Lauren Baggett Claire Bardel Erik‐Jan Kamsteeg Rolph Pfundt

Corrado Romano

Johan Aronsson Antonino Alberti Mirella Vinci

Maria J. Miranda Amy Lacroix Dragan Marjanovic Vincent Des Portes Patrick Edery Dagmar Wieczorek

Elena Gardella

Ingrid E. Scheffer

Heather Mefford Damien Sanlaville Gemma L. Carvill Gaetan Lesca

Annals of Neurology Vol. 83 No. 5 pp. 926-934 · Wiley

View at Publisher Save 10.1002/ana.25222

Abstract

ObjectiveCut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to 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).MethodsThe 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.ResultsThe cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5–21.0). 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 electroencephalogram 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 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. 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.InterpretationPatients 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. Ann Neurol 2018;83:926–934

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Details

Published: Apr 30, 2018
Vol/Issue: 83(5)
Pages: 926-934
License: View

Authors

N

Nicolas Chatron

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

R

Rikke S. Møller

Danish Epilepsy Centre, Dianalund, and University of Southern Denmark, Institute for Regional Health research Odense Denmark

N

Neena L. Champaigne

Greenwood Genetic Center Greenwood SC

A

Amy L. Schneider

Epilepsy Research Centre, Department of Medicine, Austin Health University of Melbourne Heidelberg VIC Australia

A

Alma Kuechler

Institut für Humangenetik, Universitätsklinikum, and Universität Duisburg‐Essen Essen Germany

A

Audrey Labalme

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

T

Thomas Simonet

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

L

Lauren Baggett

Greenwood Genetic Center Greenwood SC

C

Claire Bardel

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 Lyon France

E

Erik‐Jan Kamsteeg

Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands

R

Rolph Pfundt

Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands

C

Corrado Romano

Oasi Research Institute–IRCCS Troina Italy

J

Johan Aronsson

Habiliteringscentrum, Ryhov Hospital Jönköping Sweden

A

Antonino Alberti

Oasi Research Institute–IRCCS Troina Italy

M

Mirella Vinci

Oasi Research Institute–IRCCS Troina Italy

M

Maria J. Miranda

Department of Pediatrics, Pediatric Neurology Herlev University Hospital Copenhagen Denmark

A

Amy Lacroix

Department of Pediatrics, Division of Genetic Medicine University of Washington Seattle WA

D

Dragan Marjanovic

Danish Epilepsy Centre, Dianalund, and University of Southern Denmark, Institute for Regional Health research Odense Denmark

V

Vincent Des Portes

Centre de référence « Déficiences Intellectuelles de causes rares », HCL, F‐69675, Bron; ISC, CNRS UMR 5304, Bron; Université de Lyon Lyon France

P

Patrick Edery

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

D

Dagmar Wieczorek

Institut für Humangenetik, Universitätsklinikum, and Universität Duisburg‐Essen Essen Germany; Institut für Humangenetik, Universitätsklinikum Essen, Essen, and Institut für Humangenetik, Universitätsklinikum Düsseldorf Düsseldorf Germany

E

Elena Gardella

Danish Epilepsy Centre, Dianalund, and University of Southern Denmark, Institute for Regional Health research Odense Denmark

I

Ingrid E. Scheffer

Epilepsy Research Centre, Department of Medicine, Austin Health University of Melbourne Heidelberg VIC Australia; Florey Institute of Neuroscience and Mental Health The University of Melbourne VIC Australia; Department of Paediatrics, Royal Children's Hospital The University of Melbourne Parkville Victoria Australia

H

Heather Mefford

Department of Pediatrics, Division of Genetic Medicine University of Washington Seattle WA

D

Damien Sanlaville

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

G

Gemma L. Carvill

Department of Neurology Northwestern University Feinberg School of Medicine Chicago IL

G

Gaetan Lesca

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

Funding

NIH Award: NS089858

National Health and Medical Research Council

Cite This Article

Nicolas Chatron, Rikke S. Møller, Neena L. Champaigne, et al. (2018). The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant. Annals of Neurology, 83(5), 926-934. https://doi.org/10.1002/ana.25222

The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

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