Exome and targeted sequencing have revolutionized clinical diagnosis. This has been particularly striking in epilepsy and neurodevelopmental disorders, for which new genes or new variants of preexisting candidate genes are being continuously identified at increasing rates every year. A surprising finding of these efforts is the recognition that gain of function potassium channel variants are actually associated with certain types of epilepsy, such as malignant migrating partial seizures of infancy or early-onset epileptic encephalopathy. This development has been difficult to understand as traditionally potassium channel loss-of-function, not gain-of-function, has been associated with hyperexcitability disorders. In this article, we describe the current state of the field regarding the gain-of-function potassium channel variants associated with epilepsy (KCNA2, KCNB1, KCND2, KCNH1, KCNH5, KCNJ10, KCNMA1, KCNQ2, KCNQ3, and KCNT1) and speculate on the possible cellular mechanisms behind the development of seizures and epilepsy in these patients. Understanding how potassium channel gain-of-function leads to epilepsy will provide new insights into the inner working of neural circuits and aid in developing new therapies.

外显子组和靶向测序已彻底改变了临床诊断。在癫痫和神经发育疾病中，这一点尤为突出，为此，每年不断以不断增加的速度不断发现新的基因或现有候选基因的新变体。这些努力的一个令人惊讶的发现是认识到功能钾通道变异的获得实际上与某些类型的癫痫有关，例如婴儿期的恶性迁移性部分发作或早期发作的癫痫性脑病。这种发展很难理解，因为传统上钾通道功能丧失而不是功能获得已与过度兴奋性疾病有关。在本文中，我们描述了与癫痫相关的功能获得性钾通道变异的当前领域状态（KCNA2，KCNB1，KCND2，KCNH1，KCNH5，KCNJ10，KCNMA1，KCNQ2，KCNQ3和KCNT1），并推测了可能的细胞机制这些患者的癫痫发作和癫痫发展的背后。了解钾通道功能增益如何导致癫痫将为神经回路的内部工作提供新见解，并有助于开发新疗法。