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The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.

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.

SUBMITTER: Chatron N

PROVIDER: S-EPMC6021218 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.

Chatron Nicolas N Møller Rikke S RS Champaigne Neena L NL Schneider Amy L AL Kuechler Alma A Labalme Audrey A Simonet Thomas T Baggett Lauren L Bardel Claire C Kamsteeg Erik-Jan EJ Pfundt Rolph R Romano Corrado C Aronsson Johan J Alberti Antonino A Vinci Mirella M Miranda Maria J MJ Lacroix Amy A Marjanovic Dragan D des Portes Vincent V Edery Patrick P Wieczorek Dagmar D Gardella Elena E Scheffer Ingrid E IE Mefford Heather H Sanlaville Damien D Carvill Gemma L GL Lesca Gaetan G

Annals of neurology 20180430 5

<h4>Objective</h4>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).<h4>Methods</h4>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 phen ...[more]

PMID: 29630738

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The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.

Publications

The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant.

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