Abstract

Background/Objectives: In resource-limited regions, limited access to genetic testing may delay etiological diagnosis in selected patients with epilepsy and complex neurological manifestations, particularly when the phenotype raises suspicion of an underlying genetic etiology. This study aimed to assess the diagnostic value and clinical utility of phenotype-guided WES in selected patients aged ≥17 years with epilepsy and complex neurological manifestations in Southern Kazakhstan and to characterize clinical, therapeutic, and molecular features associated with drug-resistant epilepsy (DRE). Methods: This observational cohort included 78 patients aged ≥17 years with epilepsy and complex neurological manifestations identified through 25 outpatient medical centers. After enrollment, all patients underwent structured HPO-based phenotyping, assessment of antiseizure medication exposure, seizure burden, treatment response, and proband-only WES. Variants were interpreted according to ACMG/AMP guidelines. Exploratory multivariable logistic regression was used to assess factors associated with DRE. Results: P/LP variants were identified in 12/78 patients, corresponding to a diagnostic yield of 15.4%. VUS were detected in 16/78 patients (20.5%). DRE was present in 41 patients (52.6%), all of whom were receiving polytherapy. Carbamazepine was the most frequently used antiseizure medication (52/78, 66.7%), followed by valproic acid (32/78, 41.0%) and levetiracetam (20/78, 25.6%). Patients with DRE had earlier seizure onset, more frequent definite structural MRI abnormalities, and a higher proportion of P/LP variants. In the adjusted model, P/LP variant presence and definite structural MRI abnormality were associated with DRE. Conclusions: Phenotype-guided proband-only WES provided clinically relevant diagnostic information in a real-world epilepsy cohort with complex neurological manifestations in a resource-limited outpatient setting. The observed burden of DRE and polytherapy supports the potential value of integrating therapeutic profiling, neuroimaging, and genomic testing in the etiological evaluation of patients with epilepsy and additional neurological features.

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