中国人群腓骨肌萎缩症的致病基因分布对比研究——14年队列观察  

The genetic distribution in Chinese patients with Charcot-Marie-Tooth diseases:a 14-year cohort study

作　　者：刘小璇[1] 孙阿萍[1] 段晓慧[2] 张英爽[1] 樊东升[1] Liu Xiaoxuan;Sun Aping;Duan Xiaohui;Zhang Yingshuang;Fan Dongsheng(Department of Neurology,Peking University Third Hospital,Beijing 100191,China;Department of Neurology,China-Japan Friendship Hospital,Beijing 100029,China)

机构地区：[1]北京大学第三医院神经内科,北京100191 [2]中日友好医院神经内科,北京100029

出　　处：《中华神经科杂志》2022年第5期481-489,共9页Chinese Journal of Neurology

基　　金：北京大学医学部-乌尔姆大学联合项目基金(PKU2017ZC001-2);北京大学临床+X青年专项(PKU2021LCXQ019);北京大学第三医院队列建设项目(BYSYDL2021007)。

摘　　要：目的探讨中国汉族人群腓骨肌萎缩症(CMT)致病基因的分布特点,并与2013年北京大学第三医院总结的CMT基因分布数据进行比较,分析8年来CMT基因分布比例的异同。方法收集2007年1月至2021年3月于北京大学第三医院和中日友好医院诊治的CMT及其相关疾病家系520个,采用多重连接探针扩增技术检测外周髓鞘蛋白22(PMP22)基因重复和缺失突变后,采用二代基因测序包或全外显子组测序技术对上述家系的先证者进行基因检测,对阳性结果采用Sanger一代测序的方法验证。结果在520个家系中,确定了336个CMT家系的基因诊断,确诊比例从2013年的48.6%(51/105)增加到2021年的64.6%(336/520;χ2=9.54,P=0.003),其中PMP22基因重复占26.7%(139/520)、缝隙连接蛋白B1(GJB1)基因突变占8.8%(46/520)、线粒体融合蛋白2(MFN2)基因突变占5.0%(26/520)、髓鞘蛋白零(MPZ)基因突变占2.3%(12/520)、PMP22基因点突变占2.1%(11/520)、热休克蛋白B1基因突变占1.9%(10/520)、神经节苷脂诱导分化相关蛋白1(GDAP1)基因突变占1.9%(10/520)、SH3结构域和四三肽重复序列2(SH3TC2)基因突变占1.5%(8/520)、免疫球蛋白mu-DNA结合蛋白2(IGHMBP2)基因突变占1.3%(7/520)、MORC家族CW型锌指2(MORC2)基因突变占1.2%(6/520)、山梨醇脱氢酶(SORD)基因突变占1.0%(5/520),其余非常少见的基因突变家系有16个(16/520,3.1%),未确诊家系184个(184/520,35.4%)。结论与2013年相比,影响CMT最常见的3种基因仍然为PMP22、GJB1和MFN2基因,但MPZ基因突变患者的比例与其他基因如SH3TC2、GDAP1基因的差距越来越小。近年新发现的CMT致病基因如MORC2及SORD基因所占比例与IGHMBP2基因接近,应予以重视。二代测序技术提高了CMT的诊断效率,尤其是对于常染色体隐性突变导致的CMT诊断价值很大。Objective To investigate the genetic distribution of pathogenic genes of Charcot-Marie-Tooth diseases(CMT)in Chinese Han population,and compare the similarity and difference with the data in Peking University Third Hospital in 2013.Methods Five hundred and twenty families with CMT and related diseases in Peking University Third Hospital and China-Japan Friendship Hospital from January 2007 to March 2021 were collected.After peripheral myelin protein 22(PMP22)gene duplication and deletion mutations were initially detected by multiple ligation probe amplification,the probands of these families were sequenced by next-generation sequencing(NGS)gene panel or whole exome sequencing,and validated by Sanger sequencing.Results Among the 520 families,336 CMT families were genetically confirmed,and the mutation detection rate increased from 48.6%(51/105)in 2013 to 64.6%(336/520)in 2021(χ2=9.54,P=0.003).Among them,139 families had PMP22 gene duplication mutation(139/520,26.7%),46 families had gap junction beta-1(GJB1)gene mutation(46/520,8.8%),26 families had mitofusin-2(MFN2)gene mutation(26/520,5.0%),12 families had myelin protein zero(MPZ)gene mutation(12/520,2.3%),11 families had PMP22 gene point mutation(11/520,2.1%),and 10 families had heat shock protein B1 gene mutation(10/520,1.9%).There were 10 families with ganglioside induced differentiation associated protein 1(GDAP1)gene mutation(10/520,1.9%),8 families with SH3 domain and tetratricopeptide repeats 2(SH3TC2)gene mutation(8/520,1.5%),7 families with immunoglobulin mu DNA binding protein 2(IGHMBP2)gene mutation(7/520,1.3%),6 families with MORC family CW-type zinc finger 2(MORC2)gene mutation(6/520,1.2%),5 families with sorbitol dehydrogenase(SORD)gene mutation(5/520,1.0%),16 families with very rare gene mutation(16/520,3.1%)and 184 families without genetic diagnosis(184/520,35.4%).Conclusions Compared with the results in 2013,the 3 most common genes affecting CMT were still PMP22,GJB1 and MFN2 genes,but the proportion difference of patients with MPZ gene mutation

关 键 词：夏科-马里-图斯病 周围神经系统疾病 遗传 

分 类 号：R746.4[医药卫生—神经病学与精神病学]