This study aims to systematically review and analyze individual participant data to characterize the phenotypic presentations and molecular genetics of CHD2-associated epilepsy.

The CHD2 gene encodes a member of the chromodomain helicase DNA-binding family of proteins, which are crucial for chromatin remodeling and gene expression regulation. Pathogenic variants in CHD2 have been implicated in a spectrum of neurodevelopmental disorders, including early-onset developmental and epileptic encephalopathy, developmental delay (DD), intellectual disability (ID), and autism spectrum disorder (ASD). Despite growing interest in CHD2-related disorders, the full phenotypic spectrum—including epilepsy features and genotype-phenotype relationships—is not fully understood.

Data from 224 individuals with CHD2 mutations were included. Of the patients with available data, 53% (102/193) were male. Of those provided, 94% (161/172) of the cases were confirmed de novo mutations. Seizure onset ranged from 1 day to 22 years, with 62% (78/125) of the cases exhibiting photosensitivity and 34% (27/79) fever sensitivity. Comorbidities included ID (89%, 115/129), DD (85%, 141/165), ASD (49%, 68/138) and ADHD (28%, 24/85). EEG showed epileptiform activity in 88% (111/126) of the cases. MRI findings were abnormal in 20% (21/105) and normal in 80% (84/105) of the patients.

CHD2-associated epilepsy presents with considerable phenotypic variability, including variable age of seizure onset, photosensitivity, fever sensitivity and neurodevelopmental comorbidities. This review highlights the importance of comprehensive phenotypic and genotypic characterization to better understand the clinical spectrum of CHD2 variants, emphasizing the need for further investigation into the mechanisms driving phenotypic diversity.