不明病因早发癫痫性脑病的遗传学及早期诊断研究  

Study on genetics and early diagnosis of early onset epileptic encephalopathy of unknown etiology

作　　者：林馨 王珏[1] 林志[1] 陈琅[1] 陈巧彬[1] 林萌 郭馨馨 吴菲菲 Lin Xin;Wang Jue;Lin Zhi;Chen Lang;Chen Qiaobin;Lin Meng;Guo Xinxin;Wu Feifei(Department of Pediatrics,Provincial Clinical College of Fujian Medical University,Fujian Provincial Hospital,Fuzhou 350001,China)

机构地区：[1]福建医科大学省立临床学院福建省立医院儿科,福州350001

出　　处：《中华实用儿科临床杂志》2022年第15期1151-1155,共5页Chinese Journal of Applied Clinical Pediatrics

基　　金：福建省卫生健康科研人才培养项目资助计划(2019-CXB-17,2019-CXB-16)。

摘　　要：目的探究病因不明的早发癫痫性脑病(EOEE)的遗传学病因及其在早期诊断中的价值。方法前瞻性收集2018年1月至2021年1月就诊于福建省立医院门诊及住院部的60例病因不明的EOEE患儿的资料,采集外周血进行全外显子组测序及拷贝数变异(CNV)检测,分析患儿临床特点、遗传学测序结果。结果检测出EOEE相关的致病或可疑致病突变24例,包括婴儿痉挛症(10例)、Dravet综合征(3例)、吡哆醇依赖性癫痫及大田原综合征(各1例)、非已知癫痫性脑病(9例)。患儿起病年龄1 d~11个月(中位年龄4.2个月),就诊年龄2 d~4岁(中位年龄10个月),确诊年龄均控制在就诊1个月以内。发现单基因变异20例(33.3%),CNV 4例(6.7%);涉及13种基因:KCNQ2、SCN1A、SCN8A、CACNA1E、CDKL5、PPP3CA、PCDH19、TSC1、TSC2、ZEB2、ALDH7A1、DCX、HNRNPU;4例CNV异常分别为17p13.3缺失、11q23.3q25缺失、1q36.31-p36.33缺失、1q43-1q44缺失合并Xp22.33重复;共20种变异为国内外首次报道的新发位点;11q23.3q25缺失导致婴儿痉挛症为国内外首次报道;ZEB2变异导致婴儿痉挛症、PPP3CA基因导致癫痫性脑病均系国内首例报道。结论基因与CNV是EOEE患儿的重要潜在病因,病因不明时联合采用全外显子组测序和CNV测序技术检测,可提高EOEE患儿的遗传学病因诊断水平;对此类患儿早期进行遗传学检测,可以早期确诊及进行癫痫精准治疗。Objective To explore the genetic etiology and the value of early diagnosis of early onset epileptic encephalopathy(EOEE)with unknown etiology.Methods A total of 60 children with EOEE of unknown etiology were prospectively enrolled in the outpatient and inpatient departments of Fujian Provincial Hospital from January 2018 to January 2021.Peripheral blood was collected prospectively for whole-exome sequencing and copy number variation(CNV)detection to analyze the clinical characteristics and genetic sequencing results of the children.Results Twenty-four patients with EOEE-related pathogenic or suspected pathogenic mutations were detected,including infantile spasms(10 cases),Dravet syndrome(3 cases),pyridoxine-dependent epilepsy(1 case)and ohtahara syndrome(1 case),and unknown epileptic encephalopathy(9 cases).The onset age of EOEE-related patients ranged from 1 day to 11 months(median age was 4.2 months),the treatment age ranged from 2 days to 4 years(median age was 10 months),and the age of diagnosis was controlled within 1 month after treatment.There were 20 cases(33.3%)single gene variants and 4 cases(6.7%)CNV variants.A total of 13 genes were involved:KCNQ2,SCN1A,SCN8A,CACNA1E,CDKL5,PPP3CA,PCDH19,TSC1,TSC2,ZEB2,ALDH7A1,DCX and HNRNPU.The 4 CNV abnormalities were 17p13.3 deletion,11q23.3q25 deletion,1q36.31-p36.33 deletion,1q43-1q44 deletion and Xp22.33 duplication,respectively.Totally,20 mutations were new loci reported for the first time at home and abroad;11q23.3q25 deletion that resulted in infantile spasm was first reported at home and abroad.Infantile spasm caused by ZEB2 mutation and epileptic encephalopathy caused by PPP3CA gene were both reported for the first time in China.Conclusions Gene and CNV are important potential causes of children suffering from EOEE.When the etiology is unclear,the combination of whole-exome sequencing and CNV sequencing technology can improve the diagnosis level of genetic etiology of children with EOEE.The early genetic detection of these children can early diagnose and acc

关 键 词：癫痫性脑病 早发 全外显子组测序 拷贝数变异 

分 类 号：R742.1[医药卫生—神经病学与精神病学]