Abstract
BACKGROUND: Childhood neurometabolic disorders encompass a range of heterogeneous conditions often presenting with atypical or overlapping symptoms, making accurate diagnosis challenging, time-consuming, and costly. Whole exome sequencing (WES) has recently become a valuable diagnostic tool for suspected genetic or idiopathic neurometabolic disorders. This study evaluates the diagnostic utility of WES in Syrian patients with neurological and metabolic disorders, marking the first report of WES outcomes in this context. RESULTS: Among 54 patients, 42 (78%) were from consanguineous families, of whom 38 (90%) had positive WES results. WES identified pathogenic or likely pathogenic variants in 28 patients (52%) and discovered 14 novel mutations. Seventeen patients (31%) had variants of uncertain significance (VUS) aligning with their clinical presentation, and nine (17%) had negative results. WES provided clinically relevant information for 45 patients (83%), with a definitive diagnosis in 28 (52%). Additionally, WES led to diagnostic changes in 45 cases (83%) and treatment alterations in 40 cases (74%). CONCLUSION: Our findings demonstrate the high diagnostic yield of WES and its substantial impact on clinical outcomes. WES has facilitated changes in diagnosis, treatment adjustments, prognostic modifications, and preventive measures, supporting its utility in undiagnosed neurometabolic diseases. This study advocates for WES in pediatric neurometabolic cases, particularly where consanguinity is present.