CUX2 – Developmental and Epileptic Encephalopathy

CUX2 encodes a cut homeodomain transcription factor critical for dendrite branching, spine development, and synapse formation in layer II/III cortical neurons. Developmental and epileptic encephalopathy (DEE) refers to early-onset, often drug-resistant epilepsies with associated developmental impairment. Increasing evidence implicates heterozygous CUX2 variants in this spectrum.

Nine unrelated probands harboring the recurrent de novo CUX2 c.1768G>A (p.Glu590Lys) variant were identified by whole-exome sequencing (n=5) or targeted panels (n=4) with median seizure onset at 6 months (range 2 months–9 years). Phenotypes ranged from myoclonic DEE (n=3), Lennox–Gastaut syndrome (n=2), and West syndrome (n=1) to genetic generalized epilepsy or static encephalopathy; eight exhibited severe cognitive impairment, six with autistic features (PMID:29630738).

Additional de novo cases include a patient with intellectual disability, seizures, and autism carrying the same p.Glu590Lys variant (PMID:29795476) and a non-consanguineous Chinese patient with c.2834C>T (p.Thr945Met) presenting with DEE who remains seizure-free on levetiracetam (PMID:35846140).

Inheritance is autosomal dominant with all reported variants arising de novo and no familial segregation. To date, 11 probands with heterozygous deleterious CUX2 variants have been described, primarily missense altering conserved residues in CUT domains.

Functional studies demonstrate that CUX2 variants disrupt protein localization in cell culture and impair dendritic arborization in Drosophila. Cux2- and Casp-knockout mice exhibit increased susceptibility to kainate-induced seizures, elevated excitatory synaptic transmission from entorhinal cortex to hippocampus, and increased excitatory neuron numbers, supporting a loss-of-function mechanism (PMID:35581205).

Integration of strong genetic evidence—recurrent de novo variants in multiple unrelated probands—and concordant functional data establishes a Strong gene-disease association. CUX2 variant testing should be considered in early-onset, drug-resistant epileptic encephalopathies.

References

• Ann Neurol • 2018 • The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant. PMID:29630738
• European Journal of Human Genetics • 2018 • A recurrent de novo CUX2 missense variant associated with intellectual disability, seizures, and autism spectrum disorder. PMID:29795476
• Frontiers in Genetics • 2022 • Novel Variant Expands the Clinical Spectrum of CUX2-Associated Developmental and Epileptic Encephalopathies. PMID:35846140
• Scientific Reports • 2022 • CUX2 deficiency causes facilitation of excitatory synaptic transmission onto hippocampus and increased seizure susceptibility to kainate. PMID:35581205

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