Department of Pediatrics, Nowon Eulji Medical Center, Eulji University, Seoul, Republic of Korea.
Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
PLoS One. 2018 Jun 20;13(6):e0199321. doi: 10.1371/journal.pone.0199321. eCollection 2018.
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.
常考虑常见的遗传全面性癫痫综合征的遗传异质性。本研究使用下一代测序的多基因panel 测试对常见的遗传全面性癫痫综合征的潜在候选或易感基因进行了重点分析。本研究包括青少年肌阵挛性癫痫、青少年失神癫痫和单纯全面性强直-阵挛发作性癫痫患者。我们根据美国医学遗传学与基因组学学院指南确定了致病性变异，使用病例对照关联分析和家系分析对家族性病例确定了易感变异。共纳入 57 例患者，包括 51 例散发性病例和 6 例家族性病例。确定了 16 个不同基因的 22 个致病性和可能致病性变异。CACNA1H 是最常观察到的单一基因。电压门控 Ca2+通道基因的变异，包括 CACNA1A、CACNA1G 和 CACNA1H，在 32%的变异（n=7/22）中观察到。使用病例对照关联分析确定易感变异的分析表明，KCNMA1 c.400G>C 与常见的遗传全面性癫痫综合征有关。仅 1 个家系（家系 A）通过家系分析显示 CACNA1H 上存在候选致病性变异 p.(Arg788His)。本研究在约四分之一的患者（n=16/57）中确定了候选遗传变异，每位患者平均确定了 2.8 个变异。研究结果强化了常见 GGE 综合征具有高度基因座和等位基因异质性的多基因疾病假说，进一步表明电压门控 Ca2+通道是常见遗传全面性癫痫综合征的重要致病因素。本研究扩展了我们对常见遗传全面性癫痫综合征的全面认识。
