Sekwencjonowanie całego egzomu w dzieciętcej epilepsji: retrospektywne badanie z ośrodka trzeciorzędowego w Arabii Saudyjskiej
Clinical whole exome sequencing in childhood epilepsy: a tertiary center retrospective study from Saudi Arabia
W skrócie
Badacze przeanalizowali wyniki badań genetycznych 108 dzieci z epilepsją, u których przeprowadzono sekwencjonowanie całego egzomu. U 91% pacjentów znaleziono zmiany genetyczne, a u 30% udało się zidentyfikować konkretne mutacje wyjaśniające chorobę - szczególnie u dzieci z rodzin, gdzie rodzice są krewnymi. Wyniki badań genetycznych pomogły w zmianie leczenia u 5% pacjentów, a przy uwzględnieniu zmian o niejasnym znaczeniu potencjalna przydatność diagnostyczna wzrosła do 60%.
Oryginalny abstract (angielski)
Childhood epilepsy, particularly when drug-resistant, often has an underlying genetic etiology. Populations with high consanguinity rates, such as Saudi Arabia, are expected to have a higher burden of autosomal recessive disorders. However, the diagnostic yield and clinical utility of whole-exome sequencing (WES) in this context require further characterization. We conducted a retrospective cross-sectional study at King Faisal Specialist Hospital and Research Centre-Jeddah (KFSHRC-J) between May 2017 and November 2021. We reviewed charts of all patients with clinical WES results (n = 561) and included 108 pediatric patients (< 14 years) for whom epilepsy was the primary indication for testing. Data on demographics, clinical presentation, radiological findings, and WES results were extracted from electronic medical records. Variants were classified according to ACMG guidelines. Among 108 patients (53 males, 49%; 55 females, 51%), the mean age at epilepsy onset was 2.6 years, and 77% (83/108) reported consanguinity. WES identified reportable genetic findings in 98 cases (90.7%), classified as pathogenic/likely pathogenic variants (n = 32) or variants of unknown significance (VUS) (n = 66). In the remaining 10 cases (9.3%), no variant considered sufficient to explain the clinical phenotype was identified. The definitive diagnostic yield, defined as pathogenic or likely pathogenic variants explaining the clinical phenotype, was 30% (32/108; 95% CI: 22-39%). Autosomal recessive inheritance accounted for 72% (23/32) of diagnosed cases. When including VUS with strong phenotype correlation, the potential diagnostic yield increased to 60% (65/108). WES results directly influenced clinical management in 5% (5/108) of patients, including targeted metabolic therapy, medication optimization, and avoidance of contraindicated therapies. WES demonstrates significant diagnostic utility in childhood epilepsy, particularly in consanguineous populations with a high burden of autosomal recessive disorders. Integration of WES into the diagnostic workflow enables precision medicine approaches and supports early genetic counseling.