Objective: This study aimed to evaluate the diagnostic yield of whole genome sequencing (WGS) in patients with developmental epileptic encephalopathy manifesting with epileptic spasms (DEE-ES) and infantile epileptic spasms syndrome (IESS) with unknown etiology, and to assess treatment outcomes of patients with and without a genetic diagnosis.Methods: We included patients clinically diagnosed with ES, dividing them into the DEE-ES and IESS groups with no identifiable causes from prior neuroimaging, genetic, or metabolic testing. WGS was performed for all patients, and their parents underwent targeted sequencing.Results: WGS identified pathogenic or likely pathogenic variants in 15 of 56 (26.7%) patients. Specifically, the yield for the DEE-ES and IESS groups was 6 of 13 (46.7%) and 9 of 43 (20.9%), respectively. Of those with a genetic diagnosis, 12 had single nucleotide variants, 3 had copy number variants, and 1 had both. KCNQ2 was the most frequently affected gene in the DEE-ES group. Clinical management changed for 4 (26.7%) of these patients. Cessation of ES after the first treatment was similar regardless of genetic diagnosis. A clinical response to the first treatment was associated with long-term favorable seizure outcomes, particularly in the IESS group, although patients with a genetic diagnosis had a higher rate of developmental delay at the last follow-up.Conclusions: WGS identified genetic causes in 46.7% of DEE-ES patients and 20.9% IESS patients, with limited impact on clinical management. Patients in the IESS group with a genetic diagnosis exhibited poorer long-term developmental outcomes.