Liu Xiao-Rong, Bian Wen-Jun, Wang Jie, Ye Ting-Ting, Li Bing-Mei, Liu De-Tian, Tang Bin, Deng Wei-Wen, Shi Yi-Wu, Su Tao, Yi Yong-Hong, Liao Wei-Ping
Key Laboratory of Neurogenetics and Channelopathies of Guangdong Institute, Department of Neurology of the Second Affiliated Hospital of Guangzhou Medical University, of Neuroscience, Province and the Ministry of Education of China, Guangzhou, China.
Front Genet. 2020 Oct 15;11:559080. doi: 10.3389/fgene.2020.559080. eCollection 2020.
Idiopathic focal epilepsy (IFE) is a group of self-limited epilepsies. The etiology for the majority of the patients with IFE remains elusive. We thus screened disease-causing variants in the patients with IFE.
Whole-exome sequencing was performed in a cohort of 323 patients with IFE. Protein modeling was performed to predict the effects of missense variants. The genotype-phenotype correlation of the newly defined causative gene was analyzed.
Four novel heterozygous variants in , including two variants, were identified in four unrelated individuals with IFE. The variants included one truncating variant (c.1432C > T/p.Q478X) and three missense variants (c.478C > T/p.P160S, c.1239C > G/p.N413K, and c.1659T > A/p.N553K), which had no allele frequency in the gnomAD database. The missense variants were predicted to be damaging and affect hydrogen bonds with surrounding amino acids. Mutations Q478X, P160S, and N413K were associated with benign childhood epilepsy with centrotemporal electroencephalograph (EEG) spikes. P160S and N413K were located in the inner side of the enzyme active center. Mutation N553K was associated with benign occipital epilepsy with incomplete penetrance, located in the C-terminal of Domain 4. Further analysis demonstrated that previously reported biallelic mutations were associated with severe immunodeficiency and/or congenital disorder of glycosylation, commonly accompanied by neurodevelopmental abnormalities, while monoallelic mutations were associated with milder symptoms like IFE.
The genetic and molecular evidence from the present study implies that the variants identified in IFE patients lead to defects of the gene, suggesting that the gene is potentially associated with epilepsy. The genotype-phenotype relationship of mutations suggested a quantitative correlation between genetic impairment and phenotypic severity, which helps explain the mild symptoms and incomplete penetrance in individuals with IFE.
特发性局灶性癫痫（IFE）是一组自限性癫痫。大多数IFE患者的病因仍不清楚。因此，我们对IFE患者进行了致病变异筛查。
对323例IFE患者进行全外显子组测序。进行蛋白质建模以预测错义变异的影响。分析新定义的致病基因的基因型-表型相关性。
在4例无关的IFE个体中鉴定出4个新的杂合变异，包括2个变异。这些变异包括1个截短变异（c.1432C>T/p.Q478X）和3个错义变异（c.478C>T/p.P160S、c.1239C>G/p.N413K和c.1659T>A/p.N553K），它们在gnomAD数据库中没有等位基因频率。这些错义变异预计具有损害性，并影响与周围氨基酸的氢键。突变Q478X、P160S和N413K与伴有中央颞区脑电图（EEG）棘波的良性儿童癫痫相关。P160S和N413K位于酶活性中心内侧。突变N553K与具有不完全外显率的良性枕叶癫痫相关，位于结构域4的C末端。进一步分析表明，先前报道的双等位基因突变与严重免疫缺陷和/或糖基化先天性疾病相关，通常伴有神经发育异常，而单等位基因突变与IFE等较轻症状相关。
本研究的遗传和分子证据表明，在IFE患者中鉴定出的变异导致基因缺陷，提示该基因可能与癫痫相关。突变的基因型-表型关系表明遗传损伤与表型严重程度之间存在定量相关性，这有助于解释IFE患者症状较轻和外显不完全的现象。
