Genetic heterogeneity of common genetic generalized epilepsy syndromes is frequently considered. The present study conducted a focused analysis of potential candidate or susceptibility genes for common genetic generalized epilepsy syndromes using multi-gene panel testing with next-generation sequencing. This study included patients with juvenile myoclonic epilepsy, juvenile absence epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We identified pathogenic variants according to the American College of Medical Genetics and Genomics guidelines and identified susceptibility variants using case-control association analyses and family analyses for familial cases. A total of 57 patients were enrolled, including 51 sporadic cases and 6 familial cases. Twenty-two pathogenic and likely pathogenic variants of 16 different genes were identified. CACNA1H was the most frequently observed single gene. Variants of voltage-gated Ca²⁺ channel genes, including CACNA1A, CACNA1G, and CACNA1H were observed in 32% of variants (n = 7/22). Analyses to identify susceptibility variants using case-control association analysis indicated that KCNMA1 c.400G>C was associated with common genetic generalized epilepsy syndromes. Only 1 family (family A) exhibited a candidate pathogenic variant p.(Arg788His) on CACNA1H, as determined via family analyses. This study identified candidate genetic variants in about a quarter of patients (n = 16/57) and an average of 2.8 variants was identified in each patient. The results reinforced the polygenic disorder with very high locus and allelic heterogeneity of common GGE syndromes. Further, voltage-gated Ca²⁺ channels are suggested as important contributors to common genetic generalized epilepsy syndromes. This study extends our comprehensive understanding of common genetic generalized epilepsy syndromes.

Lee CG, et al. Korean J Pediatr. 2014 Jun;57(6):264-270. http://dx.doi.org/10.3345/kjp.2014.57.6.264

Background: Genetic testing is an emerging diagnostic approach in early‐onset epilepsy. Identification of the heterogeneous genetic causes of epilepsy may mitigate unnecessary evaluations and allow more accurate diagnosis and therapy. We aimed to uncover genetic causes of early‐onset epilepsy using next‐generation sequencing (NGS) to elucidate the diagnostic candidates and evaluate the diagnostic yield of targeted gene panel testing.Methods: We evaluated 116 patients with early‐onset epilepsy developed before 2 years old and normal brain imaging using a NGS‐based targeted gene panel. Variants were classified according to their pathogenicity, and the diagnostic yield of the targeted genes and associated clinical factors were determined.Results: We detected 40 disease‐causing variants with diagnostic yield of 34.5% (19 pathogenic, 21 likely pathogenic). Twelve variants were novel. The most commonly detected genes were SCN1A, associated with Dravet syndrome, and PRRT2, associated with benign familial infantile epilepsy. Other variants were identified in ARX, SCN2A, KCNQ2, PCDH19, STXBP1, DEPDC5, and SCN8A. The age of seizure onset and family history were associated with disease‐causing variants.Conclusion: Next‐generation sequencing‐based targeted testing is an effective diagnostic test, with 30%–40% comparable diagnostic yield. Patients with earlier seizure onset and family history of epilepsy were the best candidates for testing. For pediatric patients with early‐onset epilepsy, genetic diagnosis is important for accurate prognosis and treatment.