2. Academic Validation
  3. The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

  • Ann Neurol. 2018 May;83(5):926-934. doi: 10.1002/ana.25222.
Nicolas Chatron 1,  Rikke S Møller 2,  Neena L Champaigne 3,  Amy L Schneider 4,  Alma Kuechler 5,  Audrey Labalme 1,  Thomas Simonet 6,  Lauren Baggett 3,  Claire Bardel 7,  Erik-Jan Kamsteeg 8,  Rolph Pfundt 8,  Corrado Romano 9,  Johan Aronsson 10,  Antonino Alberti 9,  Mirella Vinci 9,  Maria J Miranda 11,  Amy Lacroix 12,  Dragan Marjanovic 2,  Vincent des Portes 13,  Patrick Edery 1,  Dagmar Wieczorek 5 14,  Elena Gardella 2,  Ingrid E Scheffer 4 15 16,  Heather Mefford 12,  Damien Sanlaville 1,  Gemma L Carvill 17,  Gaetan Lesca 1
Affiliations

Affiliations

  • 1 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.
  • 2 Danish Epilepsy Centre, Dianalund, and University of Southern Denmark, Institute for Regional Health research, Odense, Denmark.
  • 3 Greenwood Genetic Center, Greenwood, SC.
  • 4 Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Heidelberg, VIC, Australia.
  • 5 Institut für Humangenetik, Universitätsklinikum, and Universität Duisburg-Essen, Essen, Germany.
  • 6 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.
  • 7 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.
  • 8 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 9 Oasi Research Institute-IRCCS, Troina, Italy.
  • 10 Habiliteringscentrum, Ryhov Hospital, Jönköping, Sweden.
  • 11 Department of Pediatrics, Pediatric Neurology, Herlev University Hospital, Copenhagen, Denmark.
  • 12 Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA.
  • 13 Centre de référence « Déficiences Intellectuelles de causes rares », HCL, F-69675, Bron; ISC, CNRS UMR 5304, Bron; Université de Lyon, Lyon, France.
  • 14 Institut für Humangenetik, Universitätsklinikum Essen, Essen, and Institut für Humangenetik, Universitätsklinikum Düsseldorf, Düsseldorf, Germany.
  • 15 Florey Institute of Neuroscience and Mental Health, The University of Melbourne, VIC, Australia.
  • 16 Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Parkville, Victoria, Australia.
  • 17 Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL.
PMID: 29630738 DOI: 10.1002/ana.25222
Abstract

Objective: Cut 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).

Methods: 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.

Results: The 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.

Interpretation: 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. Ann Neurol 2018;83:926-934.

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