Here, we describe four patients suffering from a rather broad spectrum of epilepsy-related disorders, ranging from developmental and epileptic encephalopathy with intellectual disability (DEE) to genetic generalized epilepsy (GGE), which all harbor novel KCNH1 mutations. In one family, we found a weak association of a novel nonsense mutation with epilepsy, suggesting reduced penetrance, and which shows, in agreement with previous findings, that gain-of-function effects rather than haploinsufficiency are important for the pathogenicity of mutations. De novo missense variants in the pore region of the channel result in severe phenotypes presenting usually with DEE with various malformations. The potential pathogenicity of a novel KCNH1 germline mutation located outside of the critical pore domain observed in a GGE patient with a milder phenotype is supported by the fact that the very same amino acid exchange was detected as a somatic mutation in the resected brain tissue of a patient suffering from a focal cortical dysplasia type IIb. Thus, our case series broadens the phenotypic spectrum of KCNH1-associated diseases.

中文翻译：

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与癫痫相关的新型 KCNH1 突变：拓宽 KCNH1 相关疾病的表型谱

在这里，我们描述了四名患有相当广泛的癫痫相关疾病的患者，从发育性和癫痫性脑病伴智力障碍 (DEE) 到遗传性全身性癫痫 (GGE)，这些疾病都含有新的 KCNH1 突变。在一个家族中，我们发现一种新的无义突变与癫痫的弱关联，表明外显率降低，并且与之前的发现一致，这表明功能获得效应而不是单倍剂量不足对突变的致病性很重要。通道孔区域中的从头错义变异导致严重的表型，通常表现为 DEE 和各种畸形。在具有较轻表型的 GGE 患者中观察到的位于临界孔域外的新型 KCNH1 种系突变的潜在致病性得到了以下事实的支持：在切除的脑组织中检测到完全相同的氨基酸交换作为体细胞突变。患有局灶性皮质发育不良 IIb 型的患者。因此，我们的病例系列拓宽了 KCNH1 相关疾病的表型谱。