论文部分内容阅读
目的:对5个Dysferlinopathy家系进行n DYSF基因变异分析，明确其致病原因。n 方法:应用高通量测序技术进行检测，确定可疑变异后应用Sanger测序进行变异位点验证，根据美国医学遗传学及基因组学学会(American College of Medical Genetics and Genomics, ACMG)遗传变异分类标准与指南对变异的致病性进行评估。结果:高通量靶向测序和Sanger测序结果显示，5个Dysferlinopathy家系中共检测出10个n DYSF基因变异位点(5个移码变异、3个剪切区变异、1个错义变异和1个无义变异)。其中c.1375dupA(p.Met459Asnfs*15)、c.610C>T(p.Arg204X)、c.1180＋5G>A和c.1284＋2T>C为已报道过的致病性变异，而c.4008_4010delCCTinsAC(p.Leu1337Argfs*8)、c.1137_1169del(p.379_390del)、c.754 A>G (p.Thr252Ala)、c.1175_1176insGCAGAGTG(p.Met394Serfs*7)、c.3114_3115insCGGC(p.Arg1040 Profs*74)和c.1053＋3G>C为未报道过的新变异，根据ACMG遗传变异分类标准与指南，c.1137_1169del、c.1175_1176 insGCAGAGTG和c.3114_3115insCGGC为致病性变异(PVS1＋PM2＋PM3)，c.4008_4010delCCTinsAC变异为可能致病性变异(PVS1＋PM2)，c.754A>G和c.1053＋3G>C为意义不明确的变异(PM2＋PM3＋PP3)。n 结论:DYSF基因变异可能为这5个Dysferlinopathy家系患者的致病原因，新变异的检出丰富了n DYSF基因变异谱。n “,”Objective:To analyze the clinical phenotype and genetic variants in five Chinese pedigrees affected with Dysferlinopathy.Methods:Next generation sequencing (NGS) was carried out for the probands from the five pedigrees. Suspected variants were validated by Sanger sequencing. Pathogenicity of the variants was assessed based on the standards and guidelines by the American College of Medical Genetics and Genomics (ACMG).Results:Ten n DYSF gene variants (including 5 frameshift variants, 3 splicing variants, 1 missense variant and 1 nonsense variant) were detected. Among these, c. 1375dupA (p.Met459Asnfs*15), c. 610C>T (p.Arg204X), c. 1180+ 5G>A and c. 1284+ 2T>C were known to be pathogenic, while c. 4008_4010delCCTinsAC (p.Leu1337Argfs*8), c. 1137_1169del (p.379_390del), c. 754 A>G (p.Thr252Ala), c. 1175_1176insGCAGAGTG (p.Met394Serfs*7), c. 3114_3115insCGGC (p.Arg1040 Profs*74) and c. 1053+ 3G>C were unreported previously. Of the six novel variants, c. 1137_1169del, c. 1175_1176 insGCAGAGTG and c. 3114_3115insCGGC were predicted as pathogenic (PVS1+ PM2+ PM3), c. 4008_4010delCCTinsAC as likely pathogenic (PVS1+ PM2), c. 754A>G and c. 1053+ 3G>C as variants of uncertain significance based on the ACMG standards and guidelines.n Conclusion:Variants of the n DYSF gene probably underlay Dysferlinopathy in the patients among the five pedigrees. Above finding has enriched the spectrum of n DYSF gene variants.n