SCN4A基因复合杂合变异导致先天性肌无力综合征1例  

Prenatal diagnosis of a case with Congenital myasthenic syndrome due to compound heterozygous variants of SCN4A gene

作　　者：孟凡荣[1] 史云芳[1] 琚端[1] 王秀艳 董海伟[1] 李雪冰[2] 李晓洲[1] 周雪霞 Meng Fanrong;Shi Yunfang;Ju Duan;Wang Xiuyan;Dong Haiwei;Li Xuebing;Li Xiaozhou;Zhou Xuexia(Tianjin Key Laboratory of Female Reproductive Health and Birth Health,Department of Gynecology and Obstetrics,Tianjin Medical University General Hospital,Tianjin 300052,China;Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment,Tianjin Lung Cancer Institute,Department of Lung Cancer Surgery,Tianjin Medical University General Hospital,Tianjin 300052,China;Tianjin Key Laboratory of Injuries,Variations and Regeneration of the Nervous System,MoE Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System,Tianjin Neurological Institute,Tianjin Medical University General Hospital,Tianjin 300052,China)

机构地区：[1]天津医科大学总医院妇产科、天津市女性生殖健康与优生重点实验室,天津300052 [2]天津医科大学总医院肺部肿瘤外科、天津市肺癌研究所、天津市肺癌转移与肿瘤微环境重点实验室,天津300052 [3]天津医科大学总医院、天津市神经病学研究所、天津市神经损伤变异与再生重点实验室、教育部中枢创伤修复与再生重点实验室,天津300052

出　　处：《中华医学遗传学杂志》2024年第4期450-455,共6页Chinese Journal of Medical Genetics

基　　金：国家自然科学基金(81901502、81972354、82172901、82273019);天津市医学重点学科(专科)建设项目资助(TJYXZDXK-031A、TJYXZDXK-061B);天津医科大学总医院孵育基金(ZYYFY2019022);天津市自然科学基金多元投入基金项目(21JCQNJC01440);天津市自然科学基金(22JCYBJC00280)。

摘　　要：目的对1对具有3次不良孕产史的夫妇的临床资料以及先天性肌无力16型(CMS16)胎儿的遗传学特征进行分析。方法选取2018年2月因"2次不良孕产史"就诊于天津医科大学总医院的夫妇作为研究对象,回顾分析其临床资料。对其进行全外显子组测序(WES),并对候选变异进行Sanger测序验证。通过低深度全基因组测序对胎儿的染色体拷贝数变异(CNV)进行检测。结果孕妇第1胎孕27+5周晚期流产,超声检查发现胎儿胸水、羊水过多;第2胎孕30+5周超声检查发现胎儿手部畸形、胸水、羊水过多而选择引产。夫妻双方均否认遗传病家族史。孕妇第3胎CNV未见明显异常,SCN4A基因存在母源c.3172C>T(p.R1058W)和父源c.1431delG(p.K477fs*89)复合杂合变异。根据美国医学遗传学与基因组学学会(ACMG)相关指南,判断c.3172C>T(p.R1058W)为可能致病性变异(PM1+PM2_Supporting+PP3+PP4),c.1431delG(p.K477fs*89)为致病性变异(PVS1+PM2_Supporting+PP4)。结论c.3172C>T(p.R1058W)和c.1431delG(p.K477fs*89)复合杂合变异考虑是孕妇第3个胎儿的致病原因,初步诊断其为CMS16。Objective To explore the clinical and genetic characteristics of a fetus diagnosed with Congenital myasthenic syndrome type 16(CMS16).Methods A couple who had visited Tianjin Medical University General Hospital in February 2018 due to"adverse outcome of two pregnancies"was selected as the study subject.Clinical data was gathered.Peripheral blood and amniotic fluid samples were collected and subjected to whole exome sequencing(WES).Candidate variant was verified by Sanger sequencing.Low-depth whole-genome sequencing was carried out to detect copy number variation(CNV)in the fetus.Results The couple′s first pregnancy had resulted in a miscarriage at 27+5 weeks,when ultrasound had revealed pleural effusion and polyhydramnios in the fetus.Their second pregnancy was terminated at 30+5 weeks due to fetal hand malformations,polyhydramnios and pleural fluid.Both couple had denied family history of genetic conditions.For their third pregnancy,no CNV abnormality was detected,whilst a compound heterozygous variants,including a maternally derived c.3172C>T(p.R1058W)and paternal c.1431delG(p.K477fs*89)in the SCN4A gene were detected.Based on the guidelines from the American College of Medical Genetics and Genomics,the c.3172C>T(p.R1058W)was predicted as a likely pathogenic variant(PM1+PM2_supporting+PP3+PP4),whilst the c.1431delG(p.K477fs*89)was predicted as a pathogenic variant(PVS1+PM2_supporting+PP4).Conclusion The c.3172C>T(p.R1058W)and c.1431delG(p.K477fs*89)compound heterozygous variants of the SCN4A gene probably underlay the CMS16 in the third fetus.

关 键 词：肌无力综合征 先天性 SCN4A基因 骨骼肌电压门控钠通道的α亚基 功能丧失变异 

分 类 号：R746[医药卫生—神经病学与精神病学]