背景:钠通道基因(SCN)的变异与癫痫表型密切相关。我们在这项研究中的目的是评估我们三级护理中心中SCN变异患者的基因型和表型相关性。
方法:在这项回顾性研究中,我们对2018年至2022年间在我们诊所随访的SCN变异和癫痫患者进行了评估.我们的研究讨论了患者的人口统计学,癫痫发作类型,癫痫发作的年龄,SCN变体,变体的结构域和功能,磁共振成像的发现,电机,认知,和精神病合并症,以及对抗癫痫药物的反应。使用下一代测序基因组(癫痫组)或全外显子组测序进行基因检测。为了评估变体函数,我们使用了一个预测工具(https://funnc。shinyapps.io/shinyappweb/site)。为了评估蛋白质结构域,我们使用了PER查看器(http://per.broadinstitute.org/)。
结果:已经确定了23例SCN变异和癫痫患者。16名患者有SCN1A变异,六名患者有SCN2A变异,1例患者有SCN3A变异。鉴定了两种新的SCN1A变体和两种新的SCN2A变体。分析揭示了14/23的误解,6/23废话,2/23移码,和SCN中的1/23剪接位点变体。有7种预测为功能增益的变体和13种预测为功能丧失的变体。在23名患者中;11名患有Dravet综合征,6例早期婴儿发育性脑病和癫痫性脑病,三个人患有遗传性癫痫,伴有高热惊厥和谱系障碍,其中一人患有自限性家族性新生儿婴儿癫痫,1例患有自限性小儿癫痫,1例患有小儿发展型癫痫性脑病.
结论:我们的队列主要由SCN1变体组成,他们中的大多数被预测为功能丧失。Dravet综合征是最常见的表型。我们研究中使用的预测工具证明了与临床发现的总体兼容性。由于变异功能的临床表现多样,它可能有助于指导药物选择和预测结果.我们相信,这种工具将有助于临床医生预测预后和解决难治性癫痫发作的治疗挑战。
BACKGROUND: Variants in sodium channel genes (SCN) are strongly associated with epilepsy phenotypes. Our aim in this study to evaluate the genotype and phenotype correlation of patients with SCN variants in our tertiary care center.
METHODS: In this retrospective study, patients with SCN variants and epilepsy who were followed up at our clinic between 2018 and 2022 were evaluated. Our study discussed the demographics of the patients, the seizure types, the age of seizure onset, the SCN variants, the domains and the functions of the variants, the magnetic resonance imaging findings, the motor, cognitive, and psychiatric comorbidities, and the response to anti-seizure medication. Genetic testing was conducted using a next-generation sequencing gene panel (epilepsy panel) or a whole-exome sequencing. For evaluating variant function, we used a prediction tool (https://funnc.shinyapps.io/shinyappweb/ site). To assess protein domains, we used the PER viewer (http://per.broadinstitute.org/).
RESULTS: Twenty-three patients with SCN variants and epilepsy have been identified. Sixteen patients had variants in the SCN1A, six patients had variants in the SCN2A, and one patient had a variant in the SCN3A. Two novel SCN1A variants and two novel SCN2A variants were identified. The analysis revealed 14/23 missense, 6/23 nonsense, 2/23 frameshift, and 1/23 splice site variants in the SCN. There are seven variants predicted to be gain-of-function and 13 predicted to be loss-of-function. Among 23 patients; 11 had Dravet Syndrome, 6 had early infantile developmental and epileptic encephalopathy, three had genetic epilepsy with febrile seizures plus spectrum disorder, one had self-limited familial neonatal-infantile epilepsy, one had self-limited infantile epilepsy and one had infantile childhood development epileptic encephalopathy.
CONCLUSIONS: Our cohort consists of mainly SCN1 variants, most of them were predicted to be loss of function. Dravet syndrome was the most common phenotype. The prediction tool used in our study demonstrated overall compatibility with clinical findings. Due to the diverse clinical manifestations of variant functions, it may assist in guiding medication selection and predicting outcomes. We believe that such a tool will help the clinician in both prognosis prediction and solving therapeutic challenges in this group where refractory seizures are common.