STX1B基因杂合缺失致全面性癫痫伴热性惊厥附加症一家系遗传及临床分析

doi:10.12372/jcp.2025.24e1096

临床儿科杂志 ›› 2025, Vol. 43 ›› Issue (8): 628-634.doi: 10.12372/jcp.2025.24e1096

STX1B基因杂合缺失致全面性癫痫伴热性惊厥附加症一家系遗传及临床分析

姜燕丽¹, 邵新华², 邬振飞¹, 闫露露³^,⁴, 解敏³^,⁴, 庄丹燕³^,⁴, 李海波³^,⁴()

1.宁波市镇海区人民医院医疗集团儿科（浙江宁波 315202）
2.上海交通大学医学院附属新华医院小儿神经内科（上海 200092）
3.宁波市胚胎源性疾病防治重点实验室（浙江宁波 315012）
4.宁波大学附属妇女儿童医院出生缺陷综合防治中心（浙江宁波 315012）

收稿日期:2024-10-15 录用日期:2025-02-19 出版日期:2025-08-15 发布日期:2025-07-28
通讯作者: 李海波 E-mail:lihaibo-775@163.com
基金资助:
宁波市公益重点项目(2022S035);宁波市医疗卫生高端团队(2022020405);宁波市揭榜挂帅市重点研发计划项目(2023Z178)

Genetic and clinical characterization of a generalized epilepsy with febrile seizures plus family caused by heterozygous deletion of the STX1B gene

JIANG Yanli¹, SHAO Xinhua², WU Zhenfei¹, YAN Lulu³^,⁴, XIE Min³^,⁴, ZHUANG Danyan³^,⁴, LI Haibo³^,⁴()

1. Department of Pediatrics, Ningbo Zhenhai District People's Hospital Medical Group, Ningbo315202, Zhejiang, China
2. Department of Pediatric Neurology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
3. Ningbo Key Laboratory for the Prevention and Treatment of Embryogenic Diseases, Women and Children’s Hospital of Ningbo University, Ningbo315012, Zhejiang, China
4. The Central Laboratory of Birth Defects Prevention and Control, Women and Children’s Hospital of Ningbo University, Ningbo315012, Zhejiang, China

Received:2024-10-15 Accepted:2025-02-19 Published:2025-08-15 Online:2025-07-28
Contact: LI Haibo E-mail:lihaibo-775@163.com

摘要/Abstract

摘要：

目的探讨全面性癫痫伴热性惊厥附加症一家系的遗传学特点，并进行遗传及临床分析。方法收集1例2022年2月在我院神经内科就诊的热性惊厥患儿及其家庭成员的临床资料，提取患儿及其姐姐、父母的外周血DNA，通过外显子组测序（WES）技术筛选出疑似致病基因变异，针对可疑变异进行实时荧光定量多聚核苷酸链式反应（qPCR）验证及致病性分析。并对相关文献进行总结。结果先证者及其姐姐均携带STX1B基因第8~9号外显子的缺失及部分第10号外显子的缺失（STX1B exon 8-9 del, exon 10 partial del），变异遗传自母亲。先证者为2岁6个月男童，因发热伴抽搐就诊，抽搐表现为全面性强直-阵挛发作，未治疗，随访过程中再次发作1次，发作表现相似；患儿姐姐表现为癫痫，幼时也有热性惊厥史，先后服用丙戊酸钠、左乙拉西坦治疗5年，发作得到控制，无智力运动异常；患儿母亲表现为幼时热性惊厥和癫痫，曾口服抗癫痫药3年后未再发作。文献检索发现共有65例STX1B基因相关癫痫患者，涉及变异位点34个，以错义变异多见，癫痫发作类型有临床异质性，不同变异位点预后不同。结论本研究发现此家系的基因变异为STX1B基因第8~9号外显子及部分第10号外显子的杂合缺失，该变异既往未见报道。随访结果提示此次新发现的变异所致的癫痫对抗癫痫药物治疗有效，虽出现了热性惊厥的发作，但智力发育正常，无神经功能损害。

关键词: STX1B基因, 热性惊厥, 癫痫, 基因变异, 遗传学

Abstract:

Objective To investigate the genetic basis of a family with generalized epilepsy with febrile seizures plus (GEFS+) and to perform integrated genetic and clinical analysis. Methods Clinical data were collected from a pediatric patient presenting with febrile seizures and his family members who visited the Neurology Department of Women and Children's Hospital of Ningbo University in February 2022. Peripheral blood DNA was extracted from the proband, his sister, and their parents. Whole-exome sequencing (WES) was conducted to identify potential pathogenic gene variants, followed by real-time fluorescent quantitative polymerase chain reaction (qPCR) for validation and pathogenicity assessment of candidate variants. Relevant literature was also reviewed. Results Both the proband and his sister carried a heterozygous deletion spanning exons 8-9 and part of exon 10 of the STX1B gene (STX1B exon 8-9 del, exon 10 partial del), which was maternally inherited. The proband was a 2.5-year-old boy who presented with fever-associated convulsions characterized as generalized tonic-clonic seizures. Without treatment, he experienced one additional seizure during follow-up with similar features. His sister had a history of childhood febrile seizures and later developed epilepsy. She was treated with sodium valproate and levetiracetam over 5 years, resulting in seizure control, with no intellectual or motor impairments observed. The mother had a personal history of childhood febrile seizures and epilepsy, and remained seizure-free after discontinuation of antiepileptic drugs following a 3-year course. A comprehensive literature review identified 65 reported cases of STX1B-related epilepsy involving 34 distinct variant sites. Missense variants were most commonly reported. Clinical manifestations showed significant heterogeneity in seizure types, and prognosis varied depending on the specific variant. Conclusion This study identified a novel heterozygous deletion in the STX1B gene encompassing exons 8-9 and part of exon 10, which has not been previously described. Follow-up findings suggest that epilepsy associated with this newly identified variant responds well to antiepileptic drug therapy. Despite episodes of febrile seizures, no cognitive or neurological deficits were observed.

Key words: STX1B gene, febrile seizures, epilepsy, gene variation, genetics

中图分类号:

姜燕丽, 邵新华, 邬振飞, 闫露露, 解敏, 庄丹燕, 李海波. STX1B基因杂合缺失致全面性癫痫伴热性惊厥附加症一家系遗传及临床分析[J]. 临床儿科杂志, 2025, 43(8): 628-634.

JIANG Yanli, SHAO Xinhua, WU Zhenfei, YAN Lulu, XIE Min, ZHUANG Danyan, LI Haibo. Genetic and clinical characterization of a generalized epilepsy with febrile seizures plus family caused by heterozygous deletion of the STX1B gene[J]. Journal of Clinical Pediatrics, 2025, 43(8): 628-634.

图/表 4

图1

图2

图3

表1

目前STX1B基因相关癫痫的基因型及临床表型汇总"

序号	性别 /例数	基因变异	蛋白质改变	散发 /家系	临床表型	后期发育
本例	男/1 女/2	c.538_*3565del	/	家系	GTCS	正常
2^[7-8]	男/8 女/9	c.166C>T	p.Gln56*	家系	GTCS(6)，Abs(4)， AS(4)，TS(2)	正常
3^[7-8]	男/1 女/7	c.133_134insGGATGTGCATTG c.135_136AC>GA	p.K45delinsRCMIE p.L46M	家系	GTCS(5)，PS(3)，AS(3)	5例正常， 3例落后
4^[7-8]	女/1	c.140C>A	p.Ser47*	散发	uk	uk
5^[7-8]	男/1	c.657T>A	p.Val216Glu	散发	GTCS，TS，Myo，Abs	落后
6^[7-8]	女/1	c.676G>C	p.Gly226Arg	家系	GTCS，Myo，Abs， AS，TS	落后
7^[7-8]	女/1	arr[hg19]16p11.2(30，332，532-31，104，012)x1	/	散发	GTCS，Myo，AS	落后
8^[12]	男/1	c.23_26dup	p.Ser10Alafs*7	散发	GTCS	正常
9^[12]	uk/1	c.546G>A	p.Met182Ile	家系	GTCS	uk
10^[13]	男/1	arr[hg19]16p11.2 (30，943，951-32，151，753)x1	/	散发	GTCS，PS，IS，Myo	落后
11^[14]	男/2 女/1	c.705C>G	p.Asn235Lys	家系	GTCS，PS	正常
12^[7]	男/2 女/1	c.852dup	p.T285Dfs*75	家系	GTCS，TS	2例正常， 1例落后
13^[7,15]	女/2	c.733C>T	p.R245*	散发	Myo，AS，PS	正常
14^[7]	男/1	c.420C>G	p.Y140*	散发	GTCS，AS	落后
15^[7]	女/1	c.628G>A	p.E210K	家系	GTCS，Myo，Abs	落后
16^[7]	男/1	c.277A>T	p.K93*	散发	GTCS,Myo	正常
17^[7]	男/2	c.563dup	p.N189Afs*5	家系	GTCS(2)，Myo(2)， Abs(2)，TS(2)	1例正常， 1例落后
18^[7,16]	男/2	c.845T>C	p.I282T	散发	Abs，Myo，GTCS， PS，AS，TS	落后
19^[7]	女/1	c.773G>A	p.S258N	散发	uk	uk
20^[7]	女/1	c.662T>C	p.L221P	家系	GTCS，Abs，Myo，AS， PS	落后
21^[7]	男/1	c.155del	p.Q52Rfs*2	散发	GTCS，Abs，Myo，AS	落后
22^[7]	男/1	c.431G>T	p.C144F	散发	Abs	落后
23^[7]	女/1	c.736G>C	p.A246P	散发	Is	落后
24^[7]	男/1 女/1	c.(?_242)_(*3565_?)del	/	家系	GTCS(1)，Abs(1)， Myo(1)，AS(1)	落后
25^[7]	男/1	c.383del	p.Q128Gfs*2	散发	Myo	落后
26^[7]	女/1	c.782G>A	p.R261Q	散发	GTCS，PS	正常
27^[7]	女/1	c.262G>T	p.V88F	家系	GTCS，PS	正常
28^[17]	女/1	c.293G>A	p.Ser98Asn	散发	无发作	落后
29^[17]	女/1	c.165dup	p.Gln56Thrfs*3	散发	GTCS，Abs，Myo，AS	落后
30^[17]	男/1	c.537+1G>A	/	uk	GTCS，PS	正常
31^[17]	女/1	c.642_643dup	p.Phe215Cysfs*9	散发	GTCS，Myo，AS，PS	落后
32^[16]	男/1	c.280+2_280+3del	/	家系	GTCS，PS	正常
33^[16]	男/1	c.820C>G	p.L274V	家系	GTCS	正常
34^[18]	男/1 女/1	c.697G>A	p.Glu233Lys	家系	GTCS	落后正常

表1

参考文献 24

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STX1B基因杂合缺失致全面性癫痫伴热性惊厥附加症一家系遗传及临床分析

Genetic and clinical characterization of a generalized epilepsy with febrile seizures plus family caused by heterozygous deletion of the STX1B gene

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