A novel frameshift CUX2 variant in a patient with epilepsy and global developmental delay: Phenotypic and genotypic expansion

The Cut Like Homeobox 2 (CUX2) gene encodes a transcription factor critical for neuronal development. Monoallelic pathogenic CUX2 variants are associated with developmental and epileptic encephalopathy 67 (DEE67), an autosomal dominant disorder characterized by variable clinical pictures including early-onset seizures, global developmental delay, and intellectual disability. While most variants described in the literature are missense, only one frameshift variant is reported as likely pathogenic for DEE67 in the ClinVar database. In this study, we report the patient, an 8-year-old girl with clinical features compatible with DEE67, who carries a novel de novo frameshift variant, c.633_636del p.(His211Glnfs∗3), in the CUX2 gene. Although formally classified as a Variant of Uncertain Significance (VUS) based on stringent ACMG criteria, the variant is predicted to be a null allele, likely leading to CUX2 haploinsufficiency via Nonsense-Mediated Decay (NMD). Clinically, her epileptic phenotype consisted of a single generalized tonic-clonic seizure, of milder entity and more treatment-responsive than those of other reported DEE67 cases. This report expands the genotypic spectrum of CUX2-related disorders and provides further evidence supporting haploinsufficiency as a pathogenic mechanism, while describing a milder clinical presentation that broadens the phenotypic spectrum of DEE67.