Severe epilepsy phenotype with SCN1A missense variants located outside the sodium channel core region: Relationship between functional results and clinical phenotype

作者全名："Fang, Zhixu; Xie, Lingling; Li, Xue; Gui, Jianxiong; Yang, Xiaoyue; Han, Ziyao; Luo, Hanyu; Huang, Dishu; Chen, Hengsheng; Cheng, Li; Jiang, Li"

作者地址："[Fang, Zhixu; Xie, Lingling; Li, Xue; Gui, Jianxiong; Yang, Xiaoyue; Han, Ziyao; Luo, Hanyu; Huang, Dishu; Chen, Hengsheng; Cheng, Li; Jiang, Li] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Neurol,Chongqing Key Lab Pediat, Minist Educ Key Lab Child Dev & Disorders,Children, 136, Zhongshan Er Rd, Chongqing 400014, Peoples R China"

通信作者："Jiang, L (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Neurol,Chongqing Key Lab Pediat, Minist Educ Key Lab Child Dev & Disorders,Children, 136, Zhongshan Er Rd, Chongqing 400014, Peoples R China."

来源：SEIZURE-EUROPEAN JOURNAL OF EPILEPSY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000862844300006

JCR分区：Q2

影响因子：3

年份：2022

卷号：101

期号：　

开始页：109

结束页：116

文献类型：Article

关键词：SCN1A; Genotype; Phenotype; Patch clamp; Missense variants

摘要："Purpose: Most SCN1A missense variants located outside the sodium channel core region show a mild phenotype. However, there are exceptions, because of which it is challenging to determine the correlation between genotype and phenotype. In this study, we aimed to determine whether functional study could be used to determine disease severity in cases with such variants, and elucidate possible genotype-phenotype relationships.Methods: Forty-seven patients with SCN1A missense variants were recruited, and one with a Dravet syndrome phenotype with an SCN1A missense variant (c.3811T>C/ p.W1271R) located outside the core region was screened with electrophysiological tests. We also reviewed functional SCN1A studies on patients with incon-sistent phenotypes and genotypes, and studied the relationship between electrophysiological measurements and clinical phenotype.Results: Patch clamp experiments showed that the W1271R variant caused significantly reduced sodium current, decreased channel voltage sensitivity, loss of channel availability, and prolonged recovery time from inactivation compared with wild type (WT), which ultimately caused a change in loss of function (LOF). Twelve cases of severe SCN1A-related epilepsy with missense variants located outside the channel core region were also included from the functional studies. Nine patients with missense SCN1A variants showed complete (3/9) or partial (6/9) physiological LOF. Two missense SCN1A variants caused physiological gain-and-loss of function (G-LOF), and one caused decreased excitability (DE).Conclusions: Not all missense variants located outside the core region cause a mild phenotype. Although current functional studies in heterologous expression systems do not accurately reflect disease severity caused by SCN1A missense variants, they could be an effective model for generation of data to study the initial effects of SCN1A missense variants."

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