Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873–4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.

中文翻译：

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从头 SCN8A 和遗传的罕见 CACNA1H 变异与严重的发育性和癫痫性脑病相关

发育性和癫痫性脑病 (DEE) 是一组以癫痫发作和发育迟缓为特征的严重癫痫。DEE 主要归因于遗传原因，并且越来越多的病例与离子通道基因的变异有关。在这项研究中，我们报告了一名患有早期严重 DEE 的儿童。全外显子组测序显示 SCN8A 基因中有一个从头杂合变体（c.4873-4881 重复）和编码 Nav1.6 电压门控钠和 Cav3.2 的 CACNA1H 基因中的遗传杂合变体（c.952G > A）电压门控钙通道，分别。人类 Nav1.6 和 Cav3.2 通道变体的体外功能分析显示，它们的门控特性发生了轻微但显着的变化，这些变化通常分别与通道功能的增益和丢失一致。