DOK7基因突变所致先天性肌无力综合征10型的临床表型和基因型特征分析  

Analysis of clinical and genetic features of congenital myasthenic syndrome type 10 caused by DOK7 gene mutations

作　　者：林慧霞 陈洁[1] 沙瑞娟[1] Lin Huixia;Chen Jie;Sha Ruijuan(Department of Neurology,Affiliated Nanjing Brain Hospital,Nanjing Medical University,Nanjing 210029,China)

机构地区：[1]南京医科大学附属脑科医院神经内科,南京210029

出　　处：《中华神经科杂志》2024年第11期1239-1246,共8页Chinese Journal of Neurology

摘　　要：目的对DOK7基因突变所致的先天性肌无力综合征10型(CMS10)的临床表型、基因突变进行分析,并对该病进行文献复习和总结。方法回顾分析2020年1月南京医科大学附属脑科医院收治的1例确诊为CMS10患者的临床表型、基因突变结果。应用全外显子测序对患者进行高通量致病基因筛查,发现候选致病突变后,根据美国医学遗传学与基因组学学会和分子病理学协会指南对变异位点进行致病性判定,并进一步应用Sanger测序进行验证。通过PubMed、中国知网和万方数据库全面检索文献对该病进行总结。结果本例患者为51岁男性,临床表现为波动性四肢无力伴呼吸困难。经临床及全外显子测序和Sanger测序诊断为携带DOK7基因(c.1296_1311del16/c.332-1G>A)复合杂合突变的CMS10,其中c.332-1G>A为新发现的突变位点。文献复习结果显示,DOK7基因突变所致的CMS10肌无力主要累及四肢近端肌肉、中轴肌,具有数天或数月波动的特点。临床进展缓慢,病程中存在急性加重事件。在71个突变位点中,框移突变为最常见的突变类型(38.0%,27/71),错义突变次之(32.4%,23/71)。外显子7(35.2%,25/71)、外显子4(26.8%,19/71)是高频突变区域。c.1124_1127dupTGCC是最常见的突变位点(43.2%,140/324)。携带c.1124_1127dupTGCC纯合突变患者的发病年龄较复合杂合突变患者大[分别为7.5(3.6,19.8)岁、1.3(0,3.8)岁,U=350.000,P<0.001]。结论CMS10是以波动性肌无力为特点的缓慢进展的常染色体隐性遗传性疾病,肌无力分布类似肢带型肌营养不良。框移突变为DOK7基因突变所致CMS10最常见的突变类型,c.1124_1127dupTGCC(C末端)是最常见的突变位点。早期识别DOK7基因突变所致的CMS10对该疾病的治疗、预后至关重要。ObjectiveTo analyze the phenotype and genotype of congenital myasthenic syndrome type 10(CMS10)caused by DOK7 gene mutation,and to conduct a literature review and summary of this disease.MethodsA retrospective analysis of the clinical characteristics and genetic test results of a patient with CMS10 in Affiliated Nanjing Brain Hospital,Nanjing Medical University in January 2020 was conducted.Whole exon sequencing was applied to high-throughput screen the pathogenic gene in this patient.After finding candidate variants,pathogenic classification was done according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guideline.Sanger sequencing was applied to verify the mutation.Then all patients with DOK7 gene mutations were summarized by searching the literatures through PubMed,CNKI and Wanfang database.ResultsThe patient was a 51-year-old man who clinically presented with fluctuating quadriparesis and respiratory distress.He was diagnosed as CMS10 with compound mutations in DOK7(c.1296_1311del16/c.332-1G>A)by clinical information and whole exon and Sanger sequencing.And c.332-1G>A was found to be a novel mutation.Literature review showed that patients with CMS10 with DOK7 gene mutations presented dominant weakness in proximal limbs and axial muscles.Patients with CMS10 would show periodic exacerbation in disease duration with slow progression.Among 71 mutations,frameshift mutation was the most frequent type(38.0%,27/71),followed by missense mutation(32.4%,23/71).Exon 7(35.2%,25/71)and exon 4(26.8%,19/71)were the hotspot regions.c.1124_1127dupTGCC was the most frequent mutation(43.2%,140/324).The age of onset in patients with homozygous c.1124_1127dupTGCC was older than that in patients with compound heterozygous c.1124_1127dupTGCC[7.5(3.6,19.8)years vs 1.3(0,3.8)years,U=350.000,P<0.001].ConclusionsCMS10 is a slowly progressive autosomal recessive genetic disease characterized by fluctuating muscle weakness,with muscle weakness distribution similar to limb-girdle musc

关 键 词：肌无力综合征 先天性 DOK7基因 基因型 表型 

分 类 号：R741[医药卫生—神经病学与精神病学]