Objective In low- and middle-income countries (LMICs), access to trio-based whole-exome or whole-genome sequencing is limited, which may delay genetic diagnosis in developmental and epileptic encephalopathies (DEE). We used clinical features to guide targeted genetic testing and reviewed the results through multidisciplinary discussion in a Vietnamese pediatric cohort with early-onset DEE and examined its association with treatment decision-making. Methods: We prospectively enrolled 51 children aged 0–23 months with early-onset DEE at a tertiary pediatric center in Vietnam between November 2023 and April 2025. Clinical phenotyping included seizure semiology, EEG, and brain MRI. Prior to testing, patients were categorized as hypothesis-driven or non–hypothesis-driven based on clinical and paraclinical features. Targeted sequencing of 108 DEE-associated genes was performed. Variants were reviewed by geneticists and then discussed in multidisciplinary sessions including clinicians. Treatment changes and seizure outcomes were assessed six months after genetic results were disclosed. Results: Pathogenic or likely pathogenic variants were identified in 25 of 51 patients (49%). Diagnostic yield differed between the hypothesis- driven and non–hypothesis-driven groups (93.3% vs 30.6%, p < 0.001). Channelopathy-related genes accounted for the largest proportion of genetic diagnoses. Among genetically diagnosed patients, 20 of 25 had a treatment change accompanied by a ≥ 50% reduction in seizure frequency. In genotype-negative patients with infantile spasms syndrome, phenotype-guided treatment adjustment was followed by effective seizure control in most cases. Significance: In this cohort, using clinical features to guide targeted genetic testing, combined with multidisciplinary review of results, was associated with higher diagnostic yield in a hypothesis-driven subgroup and was frequently accompanied by treatment changes linked to improved seizure control.
