-Related Developmental and Epileptic Encephalopathy: Expanding the Clinical Spectrum and Deciphering the Genotype-Phenotype.

Background And Objectives: developmental and epileptic encephalopathy (-DEE), also known as -related epileptic encephalopathy, is characterized by drug-resistant epilepsy with onset within the first year of life and severe psychomotor developmental delay. The condition is poorly understood, posing significant challenges to clinical management and prognosis. This study investigated genotype and phenotype correlations of individuals with -DEE to inform clinical care.

Methods: Participants or guardians of the participants in the study were globally recruited through the WWOX Foundation where, after obtaining informed consent, questionnaires were completed for individuals with -DEE using Research Electronic Data Capture, providing clinical, demographic, and genetic information. Cases with genetically confirmed biallelic variants were included in the study. Genotypes were classified as either null/null, null/missense, or missense/missense, from which genotype-phenotype correlations were made using χ analyses with the Fisher exact test.

Results: In this study, we have collected and analyzed data from 50 individuals with biallelic variants across 45 families, identifying 25 variants that have not been previously reported. The median age of the cohort was 2.5 years, with 46% being female. The most common reported clinical features were developmental delay (96%) and seizures (90%). Individuals classified with a null/null genotype (56.8%) were more likely to have hypertonia, seizures and respiratory complications compared with individuals with null/missense (29.5%) or missense/missense (13.6%) variant genotypes.

Discussion: Using information from the largest -DEE parent-reported survey, we demonstrate a higher risk of developing seizures, respiratory complications, and hypertonia in individuals with biallelic null variants. To ensure optimal care of individuals with this rare DEE, we recommend their genotype be considered during clinical management. Future studies should consider using long-term natural history studies and detailed medical records to enable deeper phenotyping of each patient.