Tourette综合征患儿轴突蛋白1基因突变研究  

Study on neurexin 1 gene mutation in children with Tourette syndrome

作　　者：曲书慧 刘文淼 沈露 刘世国[2] 董继承[3] QU Shuhui;LIU Wenmiao;SHEN Lu;LIU Shiguo;DONG Jicheng(Qingdao Mental Health Center,Qingdao 266034)

机构地区：[1]济宁医学院,济宁270200 [2]青岛大学附属医院医学遗传科 [3]青岛市精神卫生中心精神一科

出　　处：《中国神经精神疾病杂志》2023年第10期584-590,共7页Chinese Journal of Nervous and Mental Diseases

基　　金：国家自然科学基金项目(编号:82001441,82201706,81371499);山东省自然科学基金(编号:ZR2019PH072)。

摘　　要：目的探究轴突蛋白1(neurexin 1,NRXN1)基因在Tourette综合征(Tourette syndrome,TS)患儿中的突变特点。方法纳入524例TS患儿,采集外周血提取DNA,进行NRXN1基因全部外显子靶向测序(target region sequencing)后进行Sanger测序验证,应用DNAMAN软件、SIFT、PolyPhen2、Mutation Taster、FATHMM和ClinPred对可疑变体的危害性进行生物信息学分析,最后对携带NRXN1基因变体的患儿进行基因型及表型分析。结果13例TS患者携带13个NRXN1基因变体,包括11个点突变及2个缺失突变。其中2个点突变,c.79G>T(p.A27S)和c.58G>T(p.G20C),为新发现的变体,其他9个点突变及2个缺失突变包括c.3523A>G(p.I1175V)、c.4180A>T(p.T1394S)、c.1697A>T(p.H566L)、c.3715G>A(p.A1239T)、c.878A>C(p.N293T)、c.475C>T(p.P159S)、c.320C>T(p.T107M)、c.365A>G(p.Q122R)、c.611T>A(p.L204Q)、c.68_79del(p.G23_G26del)、c.65_79del(p.G22_G26del)。生物信息学分析表明c.58G>T、c.1697A>T、c.475C>T、c.365A>G、c.878A>C、c.79G>T等6种基因变体的危害性可能相对较高。13例患儿中有6例采集到临床表现的信息,该6例患儿有不同部位的抽动,1例伴随强迫症状,1例出现情绪不稳,3例表现易激惹,6例患儿未出现重复语言、注意缺陷、多动障碍、睡眠障碍及抑郁症状的表现。结论TS患儿中检测到NRXN1基因突变位点,拓展了NRXN1突变谱。携带不同基因变体的患儿临床表现不相同,基因型及表型之间的关系需要进一步探索。Objective To explore the mutation characteristics of neurexin 1(NRXN1)gene in children with Tourette syndrome(TS).Methods A total of 524 children with TS were enrolled.DNA extracted from peripheral blood was sequenced for NRXN1 gene by using target region sequencing which was further verified by using Sanger sequencing.DNAMAN software,SIFT,PolyPhen2,Mutation Taster,FATHMM and ClinPred were used to analyze the hazard of suspected variants.Finally,the genotype and phenotype of the patients with NRXN1 gene variants were analyzed.Results We found 13 variants of the NRXN1 gene in 13 TS patients such as 11 point mutations and 2 deletion mutations including two novel point mutations:c.79G>T(p.A27S)and c.58G>T(p.G20C).The other nine point mutations and two deletion mutations were c.3523A>G(p.I1175V),c.4180A>T(p.T1394S),c.1697A>T(p.H566L),c.3715G>A(p.A1239T),c.878A>C(p.N293T),c.475C>T(p.P159S),c.320C>T(p.T107M),c.365A>G(p.Q122R),c.611T>A(p.L204Q)c.68_79del(p.G23_G26del),c.65_79del(p.G22_G26del).Bioinformatics analysis showed that the six gene variants c.58G>T,c.1697A>T,c.475C>T,c.365A>G,c.878A>C,c.79G>T were relatively harmful.There were 6 children with different parts of the tic,1 child with obsessive-compulsive symptoms,1 child with emotional instability,3 children with irritability,6 childrendid not have repetitive language,attention deficit,hyperactivity disorder,sleep disorder and depression.Conclusion NRXN1 gene mutation sites are detected in TS children,which expands the NRXN1 mutation spectrum.Children with different gene variants exhibit different clinical manifestations and the relationship between genotype and phenotype need further exploration.

关 键 词：TOURETTE综合征 NRXN1 基因 靶向测序 Sanger测序 生信分析 基因突变 表型 

分 类 号：R749.94[医药卫生—神经病学与精神病学]