KMT2E基因变异相关儿童失神癫痫临床表型及遗传学分析  

Clinical phenotype and genetic analysis of KMT2E gene variant-associated childhood absence epilepsy

作　　者：杨莉 邱世彦 尤翠平[2] 陶蕊[2] 李玉芬 车峰远[3] Yang Li;Qiu Shiyan;You Cuiping;Tao Rui;Li Yufen;Che Fengyuan(Department of Pediatric Neurology,Linyi People′s Hospital Affiliated to Xuzhou Medical University,Linyi 276003,China;Center Laboratory,Linyi People′s Hospital,Department of Neurology,Linyi People′s Hospital,Linyi 276003,China;Center Laboratory,Linyi People′s Hospital,Department of Neurology,Linyi People′s Hospital,Shandong Provincial Clinical Research Center for Geriatric Diseases,Linyi 276003,China)

机构地区：[1]徐州医科大学附属临沂市人民医院小儿神经科,临沂276003 [2]临沂市人民医院中心实验室临沂市人民医院神经内科,临沂276003 [3]临沂市人民医院中心实验室、临沂市人民医院神经内科、山东省老年疾病临床医学研究中心,临沂276003

出　　处：《中华神经科杂志》2024年第10期1111-1119,共9页Chinese Journal of Neurology

基　　金：徐州医科大学附属医院科技发展基金(XYFY202220);临沂市重点研发计划项目(2023YX0005,2022YX0008,2022YX0012);山东省医药卫生科技项目(202306010670)。

摘　　要：目的探讨KMT2E基因变异所致儿童失神癫痫临床表型及遗传学特征。方法收集临沂市人民医院小儿神经科于2023年1月收治的1例KMT2E基因变异相关儿童失神癫痫患儿的临床资料并进行随访观察,应用全外显子测序技术及Sanger测序法对患儿及其核心家系成员进行基因检测,并对变异位点进行致病性分析。以“KMT2E”为检索词查阅在线人类孟德尔遗传数据库、人类基因突变数据库、PubMed数据库、中国知网及万方数据库建库至2024年5月相关文献,总结KMT2E基因变异相关癫痫患儿的临床表型及遗传学特征。结果患儿为女性,3岁8个月时出现典型失神发作,发育正常,视频脑电图显示广泛性3 Hz左右棘慢波伴有典型失神发作,丙戊酸足量应用后发作减少,联合拉莫三嗪后发作得到控制,临床诊断为儿童失神癫痫。全外显子测序结果显示患儿存在KMT2E基因新发移码变异c.2404dup(p.Arg802Lysfs*8)(NM_182931.3),此位点目前国内外尚未报道。根据美国医学遗传学与基因组学学会变异分类标准与指南,判读c.2404dup变异为致病性变异(PVS1+PS2_Supporting+PM2_Supporting)。患儿父母、哥哥、妹妹均未携带该变异且临床表型正常。共检索到已报道KMT2E基因变异相关癫痫患者22例(包括本例共23例),其中女性10例,男性13例。皆为常染色体显性遗传,其中20例为微小变异,包括8例移码变异、7例错义变异、2例剪切变异、2例无义变异、1例同义变异,其余3例为大片段缺失(包含全基因者2例)。临床表现主要包括癫痫发作(失神发作5例,局灶性发作伴或不伴继发强直阵挛发作7例,强直阵挛发作9例,痉挛发作1例,肌阵挛发作、强直发作、失张力发作1例,出现癫痫持续状态3例,明确为难治性癫痫5例,癫痫起病年龄从新生儿期至青春期)、智力障碍(21/23,4例轻度,5例中度,5例重度)、特殊面容(11/23)、孤独症(3/23)等。结论KMT2E基因变异相ObjectiveTo explore the clinical phenotype and genetic characteristics of children with childhood absence epilepsy caused by KMT2E gene variants.MethodsThe clinical data of 1 case of KMT2E gene variant-associated childhood absence epilepsy admitted to the Department of Pediatric Neurology of Linyi People′s Hospital in January 2023 were collected and followed up,and the child and her family were genetically examined by using whole-exome sequencing and Sanger sequencing,and the pathogenicity of mutation loci was analyzed.The Online Mendelian Inheritance in Man,Human Gene Mutation Database,PubMed database,China National Knowledge Infrastructure,and Wanfang database were consulted with the search term"KMT2E"to summarize the clinical phenotype and genetics of the children with epilepsy associated with KMT2E gene variant.ResultsThe child is a female,presented with typical absence seizures at the age of 3 years and 8 months,with normal development,video electroencephalogram showing widespread spikes and slow waves around 3 Hz accompanied by typical absence seizures.Seizures decreased after valproic acid was applied at full dosage,and were controlled after combination with lamotrigine.Her clinical diagnosis of childhood absence epilepsy was made.The results of whole-exome sequencing showed that the child had a de novo frameshift variant c.2404dup(p.Arg802Lysfs*8)in the KMT2E gene(NM_182931.3),which had not yet been reported domestically or internationally.The c.2404dup variant was interpreted as a pathogenic variant(PVS1+PS2_Supporting+PM2_Supporting)according to the American Society of Medical Genetics and Genomics variant classification criteria and guidelines.Her parents,older brother and younger sister did not carry the variant and had a normal clinical phenotype.A total of 22 patients with epilepsy associated with KMT2E gene variants were retrieved(including this case,a total of 23 cases),including 10 females and 13 males.All of them were autosomal dominant inheritance,with 20 minor variations,including 8 frameshi

关 键 词：癫痫 癫痫 失神性 KMT2E基因 变异 全外显子测序 

分 类 号：R742.1[医药卫生—神经病学与精神病学]