Table_2_Validation of targeted next-generation sequencing panels in a cohort of Polish patients with epilepsy: assessing variable performance across clinical endophenotypes and uncovering novel genetic variants.DOCX

IntroductionTargeted Next-Generation Sequencing Panels (TNGSP) have become a standard in global clinical practice. Instead of questioning the necessity of next-generation sequencing in epilepsy patients, contemporary large-scale research focuses on factors such as the size of TNGSP, the comparative advantages of exome or genome-wide sequencing over TNGSP, and the impact of clinical, electrophysiological, and demographic variables on genetic test performance. This study aims to elucidate the demographic and clinical factors influencing the performance of TNGSP in 138 Polish patients with epilepsy, recognizing the pivotal role of genetic testing in guiding patient management and therapy.MethodsA retrospective analysis was conducted on patients from a genetic clinic in Poznań, Poland, who underwent commercial gene panel studies at Invitae Corporation (USA) between 2020 and 2022. Patient groups were defined based on the age of onset of the first epileptic seizures, seizure type, gender, fever dependence of seizures, presence of intellectual disability or developmental delay, abnormalities in MRI, and the presence of dysmorphic features or congenital malformations. Seizure classification followed the 2017 ILAE criteria.ResultsAmong the 138 patients, 30 (21.7%) exhibited a pathogenic or likely pathogenic variant, with a distribution of 20.7% in males and 22.5% in females. Diagnostic performance correlated with the patient’s age at the onset of the first seizure and the type of seizure. Predominant variants were identified in the SCN1A, PRRT2, CDKL5, DEPDC5, TSC2, and SLC2A1 genes. Additionally, 12 genes (CACNA1A, SCN2A, GRIN2A, KCNQ2, CHD2, DYNC1H1, NEXMIF, SCN1B, DDX3X, EEF1A2, NPRL3, UBE3A) exhibited single instances of damage. Notably, novel variants were discovered in DEPDC5, SCN1A, TSC2, CDKL5, NPRL3, DYNC1H1, CHD2, and DDX3X.DiscussionIdentified variants were present in genes previously recognized in both European and non-European populations. A thorough examination of Variants of Uncertain Significance (VUSs), specifically focusing on gene copy number changes, may unveil more extensive chromosomal aberrations. The relatively frequent occurrence of pathological variants in X chromosome-linked genes in girls warrants further investigation, challenging the prevailing notion of male predominance in X-linked epilepsy.

下一代靶向测序面板（TNGSP）已在全球临床实践中成为标准。当代大规模研究不再质疑在癫痫患者中下一代测序的必要性，而是聚焦于TNGSP的规模、外显子组或全基因组测序相较于TNGSP的相对优势，以及临床、电生理和人口统计学变量对遗传检测性能的影响。本研究旨在阐明影响138名波兰癫痫患者的TNGSP性能的流行病学和临床因素，并认识到遗传检测在指导患者管理和治疗中的关键作用。方法：对2020年至2022年间在波兰波兹南一家遗传诊所接受Invitae公司（美国）商业基因面板研究的患者进行回顾性分析。患者群体根据首次癫痫发作的年龄、发作类型、性别、发热依赖性、智力障碍或发育迟缓、MRI异常以及是否存在非典型面貌或先天性畸形进行分类。癫痫分类遵循2017年ILAE标准。结果：在138名患者中，30名（21.7%）表现出致病或可能致病的变异，其中男性占20.7%，女性占22.5%。诊断性能与患者首次癫痫发作的年龄和发作类型相关。主要的变异基因包括SCN1A、PRRT2、CDKL5、DEPDC5、TSC2和SLC2A1。此外，12个基因（CACNA1A、SCN2A、GRIN2A、KCNQ2、CHD2、DYNC1H1、NEXMIF、SCN1B、DDX3X、EEF1A2、NPRL3、UBE3A）出现了单个损伤实例。值得注意的是，在DEPDC5、SCN1A、TSC2、CDKL5、NPRL3、DYNC1H1、CHD2和DDX3X中发现新的变异。讨论：已识别的变异存在于先前在欧洲和非欧洲人群中均被认可的基因中。对不确定意义变异（VUSs）的深入分析，特别是关注基因拷贝数变化，可能会揭示更广泛的染色体异常。女孩中X染色体连锁基因中病理变异的相对频繁出现，需要进一步研究，这一发现挑战了X连锁癫痫中男性为主的普遍观念。