Characterizing CHD2-associated epilepsy: A multicenter study and pooled analysis of the literature

CHD2 variants have been implicated in a spectrum of neurodevelopmental disorders, including early-onset developmental and epileptic encephalopathy. Despite growing interest in CHD2-related disorders, the full phenotypic spectrum, including epilepsy features and genotype-phenotype relationships, is not fully understood. This study aims to systematically review the literature and analyze data from a multicenter registry to independently describe phenotypic and genotypic features of CHD2-associated epilepsy.

A systematic literature review was conducted from inception to 7/2024 using EMBASE, Web of Science, and PubMed with the keywords "CHD2". Additional data was collected from a search of the Pediatric Epilepsy Research Consortium (PERC) Epilepsy Genetics Database and the same parameters were used to gather relevant information about patients with both CHD2 variants and epilepsy.

Of the 644 screened articles, 74 articles containing individual participant data were included for full-text review and analysis, focusing on parameters such as CHD2 variants, clinical characteristics, neuroimaging findings, and electroencephalography (EEG) results. Data from 236 individuals with epilepsy and CHD2 variants were included, including 12 previously unreported cases from the PERC Genetics database. Of the patients with available data, 53% (108/205) were male, and 95% (170/179) had confirmed de novo mutations. Seizure onset ranged from 1 day to 22 years, with 59% (80/136) of the cases exhibiting photosensitivity and 37% (33/90) fever sensitivity. Most common comorbidities included intellectual disability (86%, 121/141), developmental delay (88%, 156/177), and autism (45%, 68/150). EEG showed epileptiform abnormalities in 88% (122/138) of the cases. MRI findings were abnormal in 19% (22/116) of patients.

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