Yan Hong-Jun, Liu Wen-Hui, Xu Min-Xing, Wang Peng-Yu, Gu Yu-Jie, Li Hua, Guo Jing, Luo Sheng
Epilepsy Center, Guangdong Sanjiu Brain Hospital, Guangzhou, Guangdong, China.
Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
Front Genet. 2025 Mar 31;16:1499716. doi: 10.3389/fgene.2025.1499716. eCollection 2025.
Epilepsy with febrile seizures plus (EFS+) is a syndrome with a strong genetic component. Previously, variants in several genes encoding ion channels have been associated with EFS+. However, the etiology in the majority of patients remains undetermined.
Trio-based whole-exome sequencing was performed on a patient with EFS+. Previously reported variants were systemically reviewed to analyze the phenotypic spectrum and core phenotypes.
A novel variant (c.415G>A/p.Gly139Arg) was identified in a patient with EFS+, neurodevelopmental abnormalities, and hypertrichosis. The identified variant was absent in normal populations, indicated to alter hydrogen bonds with surrounding residues by various protein modeling, predicted to be damaging for protein function by twenty algorithms, located in residues of high conservation across species, and classified as pathogenic by the ACMG guidelines. Protein modeling analyses of the variant suggested a possible gain-of-function effect. Analysis of other eight cases with variants outlined the phenotypic spectrums of , ranging from mild benign epilepsy, EFS+ with neurodevelopmental abnormalities, to syndromic neurodevelopmental disorders and revealed neurodevelopmental abnormalities and epilepsy as its core phenotypes. Integrated analysis suggested that minor allele frequency and meta-predictors effectively distinguish pathogenic variants.
This study suggested the gene as a novel candidate causative gene of EFS+, which would be helpful for the genetic diagnosis and clinical management of patients.
伴有热性惊厥附加症的癫痫（EFS+）是一种具有强大遗传成分的综合征。此前，几个编码离子通道的基因中的变异已与EFS+相关联。然而，大多数患者的病因仍未确定。
对一名EFS+患者进行了基于三联体的全外显子组测序。对先前报道的变异进行了系统回顾，以分析表型谱和核心表型。
在一名患有EFS+、神经发育异常和多毛症的患者中鉴定出一种新的变异（c.415G>A/p.Gly139Arg）。该变异在正常人群中不存在，通过各种蛋白质建模表明其会改变与周围残基的氢键，二十种算法预测其对蛋白质功能具有损害性，位于跨物种高度保守的残基中，并根据ACMG指南被分类为致病性变异。对该变异的蛋白质建模分析表明可能存在功能获得效应。对其他八例有变异的病例进行分析，勾勒出了从轻度良性癫痫、伴有神经发育异常的EFS+到综合征性神经发育障碍的表型谱，并揭示神经发育异常和癫痫是其核心表型。综合分析表明，次要等位基因频率和元预测因子可有效区分致病性变异。
本研究提示该基因是EFS+的一个新的候选致病基因，这将有助于患者的基因诊断和临床管理。
