Background: Mutations in the dysferlin (DYSF) gene cause 3 different phenotypes of muscular dystrophies: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal anterior compartment myopathy. Abstract:Obj...Background: Mutations in the dysferlin (DYSF) gene cause 3 different phenotypes of muscular dystrophies: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal anterior compartment myopathy. Abstract:Objective: To present the results of clinical and molecular analysis of 8 patients with dysferlinopathy from 5 unrelated families. Design: Clinical assessment was performed with a standardized protocol. A muscle biopsy specimen was obtained and studied by immunohistochemistry. Genetic analysis was performed using single-stranded conformation polymorphism and direct sequencing of genomic DNA. Results: All the patients presented the R1905X mutation in the DYSF gene in homozygosity, and the haplotype analysis at the DYSF locus revealed that it was a novel and founder mutation. A C-to-T transition at nucleotide position 6086 changes an arginine into a stop codon, leading to premature termination of translation. This mutation was expressed as 3 different clinical phenotypes (limb-girdle muscular dystrophy type 2B, Miyoshi distal myopathy, and distal anterior dysferlinopathy), but only 1 phenotype was found in the same family. Conclusions: The new R1905X DYSF founder mutation produced the 3 possible dysferlinopathy phenotypes without intrafamilial heterogeneity. This homogeneous population in Sueca, Spain, should be helpful in studying the modifying factors responsible for the phenotypic variability.展开更多
目的对5个Dysferlinopathy家系进行DYSF基因变异分析,明确其致病原因。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 Ge...目的对5个Dysferlinopathy家系进行DYSF基因变异分析,明确其致病原因。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)。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DYSF基因变异谱。展开更多
目的对两个遗传性肢带型肌营养不良2B型（limb-girdle muscular dystrophy type 2B,LGMD2B）家系进行致病基因突变分析。方法分别获取两例先证者及其家系成员的外周血，提取DNA，应用高通量测序和Sanger测序筛查两个家系DYSF基因的突变...目的对两个遗传性肢带型肌营养不良2B型（limb-girdle muscular dystrophy type 2B,LGMD2B）家系进行致病基因突变分析。方法分别获取两例先证者及其家系成员的外周血，提取DNA，应用高通量测序和Sanger测序筛查两个家系DYSF基因的突变位点，并分析突变位点的致病性。结果共发现DYSF基因的4个致病突变，其中1个为新发突变，3个未见临床致病报道。家系1先证者的DYSF基因存在复合杂合突变c．1667T〉C（P．Leu556Pro；遗传自父亲）以及c．5567T〉A（P．Val1856Glu；遗传自母亲）；家系2的先证者亦携带复合杂合突变c．4853A〉G（P．Tyr1618Cys；遗传自母亲）以及c．4876G〉A（P．Val1626Ile；遗传自父亲）。结论两个家系中患者的发病原因均为DYSF基因的复合杂合突变。高通量测序对于遗传性肌病的基因诊断具有重要的价值。展开更多
文摘Background: Mutations in the dysferlin (DYSF) gene cause 3 different phenotypes of muscular dystrophies: Miyoshi myopathy, limb-girdle muscular dystrophy type 2B, and distal anterior compartment myopathy. Abstract:Objective: To present the results of clinical and molecular analysis of 8 patients with dysferlinopathy from 5 unrelated families. Design: Clinical assessment was performed with a standardized protocol. A muscle biopsy specimen was obtained and studied by immunohistochemistry. Genetic analysis was performed using single-stranded conformation polymorphism and direct sequencing of genomic DNA. Results: All the patients presented the R1905X mutation in the DYSF gene in homozygosity, and the haplotype analysis at the DYSF locus revealed that it was a novel and founder mutation. A C-to-T transition at nucleotide position 6086 changes an arginine into a stop codon, leading to premature termination of translation. This mutation was expressed as 3 different clinical phenotypes (limb-girdle muscular dystrophy type 2B, Miyoshi distal myopathy, and distal anterior dysferlinopathy), but only 1 phenotype was found in the same family. Conclusions: The new R1905X DYSF founder mutation produced the 3 possible dysferlinopathy phenotypes without intrafamilial heterogeneity. This homogeneous population in Sueca, Spain, should be helpful in studying the modifying factors responsible for the phenotypic variability.
文摘目的对5个Dysferlinopathy家系进行DYSF基因变异分析,明确其致病原因。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)。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DYSF基因变异谱。
文摘目的对两个遗传性肢带型肌营养不良2B型（limb-girdle muscular dystrophy type 2B,LGMD2B）家系进行致病基因突变分析。方法分别获取两例先证者及其家系成员的外周血，提取DNA，应用高通量测序和Sanger测序筛查两个家系DYSF基因的突变位点，并分析突变位点的致病性。结果共发现DYSF基因的4个致病突变，其中1个为新发突变，3个未见临床致病报道。家系1先证者的DYSF基因存在复合杂合突变c．1667T〉C（P．Leu556Pro；遗传自父亲）以及c．5567T〉A（P．Val1856Glu；遗传自母亲）；家系2的先证者亦携带复合杂合突变c．4853A〉G（P．Tyr1618Cys；遗传自母亲）以及c．4876G〉A（P．Val1626Ile；遗传自父亲）。结论两个家系中患者的发病原因均为DYSF基因的复合杂合突变。高通量测序对于遗传性肌病的基因诊断具有重要的价值。
