Whole Exome Sequencing Based Diagnostics in Complex Childhood Epilepsy Syndromes-A Cohort Study on Clinical Utility

Studies from the subcontinent on the utility of Whole Exome Sequencing (WES) in electro-clinical phenotypes of childhood-onset drug-resistant epilepsy (DRE) syndromes, particularly the developmental and epileptic encephalopathies (DEE), are rare in the literature. Patients with DRE phenotypes of presumed genetic etiology with an age of onset of epilepsy < 12 years, with/without developmental encephalopathy, were included in this study. Our study cohort (N = 175) included 158 trios, 6 duos, and 11 proband-only samples. Age at onset of seizures was ≤ 3 years in 76.6% and > 3 years in 23.4%, with developmental delay noted in 80.6% of the cohort. The overall yield of pathogenic/likely pathogenic variants in WES was 38.9% (68/175, 19 were novel); for trio-WES it was 41.1%. Predominantly de novo variants accounted for 45 out of 68 cases (66.2%), and the most frequent disease-causing variants were missense (74%). Younger age at onset of epilepsy, female gender and electroclinical diagnosis of Dravet syndrome were associated with a higher yield as opposed to focal epilepsies. Precision medicine was considered tenable in 25/68 (36.8%) cases. Our study reveals a significant yield of trio-WES for de novo variants in childhood-onset DRE/DEE. Female gender, early age at onset, and specific electro-clinical phenotypes have a higher likelihood of identifying a monogenic etiology.