24例KCNQ2基因变异癫痫患儿的临床表型与基因型分析

doi:10.12372/jcp.2025.23e1140

摘要/Abstract

摘要：

目的探讨KCNQ2基因（OMIM#602235）变异癫痫患儿的临床表型及基因特点。方法回顾性分析2018年10月至2022年11月经外显子测序发现的KCNQ2基因阳性癫痫患儿的临床资料，总结基因型特点及治疗情况。结果 24例KCNQ2基因变异（NM_172107）癫痫患儿中，男14例、女10例。癫痫首次发作年龄为生后17小时~5岁，其中≤6个月的16例（66.7%）。根据临床预后分为良性家族性新生儿癫痫（BFNE）1例，良性家族性婴儿癫痫（BFIE）6例，不能分类的自限性癫痫综合征4例；KCNQ2-发育性癫痫性脑病（KCNQ2-DEE）13例。基因变异以错义突变为主（62.5%），同时发现7个新的KCNQ2突变位点，其中c.1411C>T评估为致病性变异，c.602G>C、c.1031G>A、c.2159_2173del（p.720_725delinsR）评估为可疑致病变异。24例患儿的中位随访时间为40个月，13例KCNQ2-DEE存在不同程度的发育迟缓，其余11例总体预后较好，认知发育正常。结论 KCNQ2变异患儿癫痫发病年龄主要为新生儿期及婴儿早期。KCNQ2-DEE预后差。建议婴幼儿期不明原因的癫痫发作应尽早行基因检测，以明确诊断。

关键词: KCNQ2基因, 良性家族性新生儿癫痫, 良性家族性婴儿癫痫, 早发癫痫性脑病, 钾通道

Abstract:

Objective To investigate the clinical and genetic characteristics of children with epilepsy caused by variations of the KCNQ2 gene (OMIM #602235). Methods The clinical data of 24 children with KCNQ2 gene variants (NM_172107) detected by whole-exome sequencing (WES) from October 2018 to November 2022 were analyzed, and the genotypic characteristics and treatment were analyzed. Results A total of 24 children (14 boys and 10 girls) with epilepsy caused by KCNQ2 gene variations were included. The age of the first seizure in these children ranged from 17 hours after birth to 5 years old. Among them, 16 children (66.7%) were younger than 6 months. According to the clinical prognosis, there were 1 case of benign familial neonatal epilepsy (BFNE), 6 cases of benign familial infantile epilepsy (BFIE), 4 cases of self-limited epilepsy syndrome that could not be classified, and 13 cases of KCNQ2-related developmental and epileptic encephalopathy (KCNQ2-DEE). The main genetic variation was missense mutation (62.5%), and 7 new KCNQ2 mutation sites were found. Among them, c.1411C>T was evaluated as pathogenic, c.602G>C, c.1031G>A, c.2159_2173del (p.720_725delinsR) was evaluated as likely pathogenic. The median follow-up time of the 24 patients was 40 months. 13 patients had varying degrees of developmental delay in KCNQ2-DEE, and the remaining 11 patients had good overall prognosis and normal cognitive development. Conclusions The age of seizures associated with KCNQ2 variation is mainly distributed in the neonatal period and early infancy. The prognosis of KCNQ2-DEE is poor. It is recommended that genetic testing should be performed as early as possible for the diagnosis of unexplained seizures in infancy.

Key words: KCNQ2 gene, benign familial neonatal epilepsy, benign familial infantile epilepsy, early-onset epileptic encephalopathy, potassium channel

王丽辉, 崔丽平, 杨花芳, 刘兰, 唐晓娜, 赵青, 王欣, 李宝广. 24例KCNQ2基因变异癫痫患儿的临床表型与基因型分析[J]. 临床儿科杂志, 2025, 43(2): 93-98.

WANG Lihui, CUI Liping, YANG Huafang, LIU Lan, TANG Xiaona, ZHAO Qing, WANG Xin, LI Baoguang. Clinical phenotype and genotype analysis of 24 epileptic children with KCNQ2 gene variation[J]. Journal of Clinical Pediatrics, 2025, 43(2): 93-98.

图/表 2

表1

KCNQ2基因变异癫痫患儿24例临床资料"

患儿	性别	起病年龄	发作类型	视频脑电图	头颅MRI	癫痫综合征	药物治疗	随访时长	发育情况
例1	女	3月24天	强直-阵挛	正常	正常	BFIE	OXC	38个月	正常
例2	女	3月4天	强直-阵挛	界线性	正常	BFIE	LEV、PB	62个月	正常
例3	女	1岁2月	强直-阵挛	高度失律	正常	IS	TPM、ACTH	26个月	落后
例4	男	3岁	阵挛	后头部为主的局灶性放电	正常	DEE	OXC	29个月	落后
例5	女	3月4天	局灶性强直	棘波、棘慢波发放	正常	BFIE	LEV	57个月	正常
例6	女	3月22天	强直-阵挛	双侧rolandic区少量尖波、尖慢波发作，双侧颞区局灶性发作	髓鞘化延迟	BFIE	OXC	37个月	正常
例7	女	2月24天	强直-阵挛	睡眠期多灶性棘波、尖棘波	苍白球稍长T2信号	BFIE	LEV、PB	24个月	正常
例8	男	10月10天	强直	双侧额极或枕、后颞区1.5~2.0Hz慢波发放	苍白球稍长T2信号，侧脑室脑白质量减少	LGS	LEV、PB	53个月	落后
例9	男	5月23天	强直-阵挛	睡眠期多灶性棘波、棘慢波发放，后头部突出	胼胝体薄，脑室周围白质T2信号稍高	DEE	LEV	13个月	落后
例10	女	2岁2月	强直-阵挛	界线性，4~5Hz慢波阵发	正常	自限性	未用药	48个月	正常
例11	男	3月6天	强直-阵挛	各期双侧后头部棘波，棘慢波不同步发放	胼胝体嘴部体积小，膝部薄	BFIE	LEV	41个月	正常
例12	男	生后17h	强直-阵挛	双侧前头部尖波，尖慢波发放，右侧突出	正常	DEE	LEV	72个月	语言落后
例13	男	生后15天	强直-阵挛	双侧前头部尖波，尖慢波发放，右侧突出	正常	DEE	LEV、PB、OXC	120个月	智力低下
例14	男	生后5天	强直-阵挛	脑电发育轻度延迟	双额顶长T2信号，苍白球稍短T1信号	BFNE	LEV、OXC	39个月	正常
例15	男	1岁	强直-阵挛	高度失律	正常	IS	VPA、LEV、LTG、CZP、TPM、泼尼松	45个月	落后
例16	男	1月	强直-阵挛	高度失律	正常	IS	TPM、硝西泮	47个月	落后
例17	男	生后4天	强直-阵挛	左侧前头部起始的局灶进展，双侧强直-阵挛	正常	DEE	LEV	31个月	落后
例18	男	2岁7月	局灶性阵挛	界线性	正常	自限性	TPM、VPA	47个月	正常
例19	女	1岁	局灶性阵挛	Rolandic区棘波、棘慢波不同步发放，颞区突出	正常	DEE	LEV、VPA	48个月	落后
例20	女	5岁	局灶性阵挛	双侧枕区棘波、棘慢波发放，左侧突出，睡眠期增多	正常	自限性	未用药	36个月	正常
例21	男	2月2天	强直-阵挛	全程爆发抑制图像	双侧大脑半球皮层薄	OS	LEV、PB、TPM、VPA	6个月	落后
例22	女	生后20天	阵挛	醒睡各期双侧后头部棘波、棘慢波发放	正常	DEE	OXC、PB	9个月	落后
例23	男	生后1天	强直	睡眠期多灶性尖波、尖慢波发放	苍白球T1高信号	DEE	LEV、PB、OXC	12个月	落后
例24	男	3月25天	强直	左侧前头部尖波散发，睡眠期左侧前头部为主局灶性发放	正常	自限性	VPA	42个月	正常

表1

表2

24例KCNQ2基因变异癫痫患儿的基因型"

患儿	突变位点	氨基酸变化	突变类型	新/已知突变	突变来源	ACMG评级依据
例1	c.1783C>T	p.R595W	错义突变	已知	新生	LP（PS2+PM2+PP3）
例2	c.1160dupC	p.L388 Afs*13	移码突变	已知	新生	P（PVS1+PS4+PM6+PM2）
例3	c.2345G>A	p.R782Q	错义突变	新	母源	VUS（PP2+BP4）
例4	c.2159_2173del	p.720_P724delinsR	整码突变	新	母源	VUS（PM2）
例5	exon2-5 del	-	外显子缺失突变	已知	新生	P（PVS1+PS4+PM2）
例6	c.2605_2609del	p.G869QfsX36	移码突变	新	新生	P（PVS1+PS2+PM1+PM2）
例7	c.1658G>A	p.R553Q	错义突变	已知	新生	P（PS1+PS2+PM2+PP3）
例8	c.602G>C	p.R201P	错义突变	新	新生	LP（PM1+PM5+PP3+PM2）
例9	c.1545G>C	p.E515D	错义突变	已知	母源	LB（BS1）
例10	c.2159_2173del	p.720_725delinsR	整码突变	新	母源	LP（PM1+PM2+PM4）
例11	c.532G>A	p.Ala178Thr	错义突变	已知	新生	LP（PS2+PM2+PP3）
例12	c.1411C>T	p.Q471X	无义突变	新	母源	LP（PVS1+PM2）
例13	c.1075A>T	p.T359S	错义突变	已知	母源	VUS（PM2+PP3）
例14	c.1031G>A	p.W344X	无义突变	新	母源	LP（PVS1+PM2）
例15	c.1545G>C	p.E515D	错义突变	已知	父源	LB（BS1）
例16	c.997C>T	p.R333W	错义突变	已知	新生	P（PS1+PS2+PM2+PP3）
例17	c.1A>G	p.Met1Va	起始密码子突变	已知	父源	P（PVS1+PM2+PM5+PP1）
例18	c.1545G>C	p.E515D	错义突变	已知	父源	LB（BS1）
例19	c.1966G>A	p.E656K	错义突变	已知	母源	P（PS1+PS2+PM2+PP3）
例20	c.1742G>A	p.R581Q	错义突变	已知	新生	P（PS1+PS2+PM2+PP3）
例21	c.601C>T	p.R201C	错义突变	已知	新生	P（PS2+PS4+PM1+PM2）
例22	c.1679G>A	p.R560Q	错义突变	已知	新生	P（PS4+PM5+PS2+PP2+PP3）
例23	c.1A>C	p.R346C	错义突变	已知	新生	P（PS1+PS2+PM2+PP3）
例24	c.2603_2604insTGGGC	p.R871GfsX60	移码突变	已知	父源	P（PVS1+PS1+PM2）

表2

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