目的：KCNH1变异体的基因型-表型相关性仍然难以捉摸。本研究旨在扩大KCNH1的表型谱，探讨癫痫与分子亚区域位置的相关性。
方法：我们对98例常见的高热惊厥（FS）或病因不明的癫痫患者进行了全外显子组测序。通过蛋白质建模和多个计算机模拟工具预测变体的损伤效应。分析所有报告的具有详细神经系统表型的KCNH1致病性变异的患者，以评估基因型-表型相关性。
结果：在三例病例中发现了两种新的KCNH1变体，包括两名具有遗传性变异的FS患者(p.Ile113Thr）和一个男孩患有从头变异的癫痫（p。Arg357Trp）。变体Ile113Thr位于eag域内，和变体p.Arg357Trp分别位于KCNH1的跨膜结构域4中。2例患者出现难治性癫痫持续状态（SE），其中1例死于SE所致急性脑病。对51例患者的30个变异的进一步分析表明，从头变异与癫痫性脑病有关，而马赛克/体细胞或种系变异导致孤立的癫痫/FS。所有与癫痫性脑病相关的热点变异聚集在跨膜域（S4和S6），而孤立性癫痫/癫痫发作或无癫痫的TBS/ZLS患者则分散在KCNH1中。
结论：我们在三个孤立的FS/癫痫患者中发现了两个新的KCNH1错义变异。KCNH1的变体引起一系列癫痫性疾病，从良性形式的遗传性孤立性癫痫/FS到难治性癫痫性脑病。基因型和变异位置有助于解释KCNH1变异患者的表型变异。
Genotype-phenotypic correlation of KCNH1 variant remains elusive. This study aimed to expand the phenotypic spectrum of KCNH1 and explore the correlations between epilepsy and molecular sub-regional locations.
We performed whole-exome sequencing in a cohort of 98 patients with familiar febrile seizure (FS) or epilepsy with unexplained etiologies. The damaging effects of variants were predicted by protein modeling and multiple in silico tools. All reported patients with KCNH1 pathogenic variants with detailed neurological phenotypes were analyzed to evaluate the genotype-phenotype correlation.
Two novel KCNH1 variants were identified in three cases, including two patients with FS with inherited variant (p.Ile113Thr) and one boy with epilepsy with de novo variant (p.Arg357Trp). Variant Ile113Thr was located within the eag domain, and variant p.Arg357Trp was located in transmembrane domain 4 of KCNH1, respectively. Two patients experienced refractory status epilepticus (SE), of which one patient died of acute encephalopathy induced by SE. Further analysis of 30 variants in 51 patients demonstrated that de novo variants were associated with epileptic encephalopathy, while mosaic/somatic or germline variants cause isolated epilepsy/FS. All hotspot variants associated with epileptic encephalopathy clustered in transmembrane domain (S4 and S6), while those with isolated epilepsy/seizures or TBS/ZLS without epilepsy were scattered in the KCNH1.
We found two novel missense variants of KCNH1 in three individuals with isolated FS/epilepsy. Variants in the KCNH1 cause a spectrum of epileptic disorders ranging from a benign form of genetic isolated epilepsy/FS to intractable form of epileptic encephalopathy. The genotypes and variant locations help explaining the phenotypic variation of patients with KCNH1 variant.
