The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

Area of Science:

• Neuroscience
• Genetics
• Epilepsy Research

Background:

• The CUX2 transcription factor is crucial for neuronal development, including dendrite branching and synapse formation in the cerebral cortex.
• Developmental and epileptic encephalopathy (DEE) encompasses severe early-onset epilepsy syndromes with significant cognitive impairment.

Purpose of the Study:

• To identify novel genetic causes of developmental and epileptic encephalopathy (DEE).
• To characterize the clinical and genetic features of patients with a specific CUX2 gene variant.

Main Methods:

• Whole-exome sequencing and targeted gene panels were used to identify the genetic variant.
• Electroclinical and neuroimaging phenotyping was performed on affected individuals.

Main Results:

• A recurrent de novo CUX2 p.Glu590Lys variant was identified in 9 patients (7 males, 2 females).
• The cohort presented with early-onset epilepsy (median onset 6 months), drug-resistant seizures, and severe cognitive impairment, with 6 patients exhibiting autistic features.
• The identified variant affects a conserved residue in the CUX2 CUT domain, potentially disrupting DNA binding and impacting neuronal development.

Conclusions:

• The CUX2 p.Glu590Lys variant represents a novel genetic cause of DEE, associated with a spectrum of generalized epilepsy and developmental encephalopathy.
• The findings highlight the critical role of CUX2 in human brain development and the genetic basis of severe early-onset epilepsy syndromes.