Identification of De Novo ZBTB18 Variant in a Patient With Global Developmental Delay, Seizures, and Juvenile Facies

Background ZBTB18 encodes a C2H2‐type zinc finger protein that acts as a transcriptional repressor and is essential for neurodevelopment. Variants in ZBTB18 are associated with intellectual developmental disorder, autosomal dominant 22 (MRD22). Patients with MRD22 present with intellectual disability (ID), corpus callosum anomalies, hypotonia, microcephaly, growth problems, epilepsy, and variable facial dysmorphism. Methods Whole exome sequencing (WES) was performed to identify the molecular etiology. Sanger sequencing was used to validate the variant. Clinical assessments were conducted using brain magnetic resonance imaging (MRI) and electroencephalogram (EEG). Results Our patient presented with sleep‐associated focal motor seizures, characterized by right‐sided clonic movements with impaired consciousness, accompanied by atypical absence seizures. She also exhibited global developmental delay, unexplained ankle hypertonia, and unique juvenile facies (characterized by a lack of complex emotional expression, a fixed gaze, and an overall immature facial gestalt). Video EEG demonstrated hypsarrhythmia, whereas brain MRI revealed no structural abnormalities at the age of 2.5 years. The patient received antiepileptic therapy, and seizure control was successfully achieved following perampanel treatment. A de novo ZBTB18 variant (NM_205768.3: c.1474delA (p.Arg492Aspfs∗11)) was identified in our patient. Conclusion To conclude, we report a de novo ZBTB18 frameshift variant (NM_205768.3: c.1474delA (p.Arg492Aspfs∗11)) in a female patient presenting with global developmental delay, epilepsy, ankle hypertonia, and unique juvenile facies. Notably, seizures were ultimately controlled with perampanel, which may provide a therapeutic insight for drug‐resistant epilepsy in MRD22. Our study expands the phenotypic and genetic spectrum of ZBTB18 and provides novel insights into the clinical management of MRD22.