The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant PMID: 29630738

Target-related Cytokines

2026-09-23

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

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.

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.