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目的:报告1例由n LMNA基因错义变异所致的先天性肌营养不良症(congenital muscular dystrophy，CMD)，并分析该错义变异的致病性。n 方法:对患儿行肌肉活检术；肌肉组织行HE、免疫化学染色以及电镜检查以明确其临床诊断；同时提取患儿及其父母外周血中DNA物质，进行全外显组测序法(trio-whole exome sequencing, trio-WES)检测以明确肌病基因诊断，并通过Sanger测序法验证检出变异，对检出变异进行生物信息学预测。结果:患儿肌肉活检组织在光镜和电镜下均可见大量的坏死肌纤维组织伴炎症细胞浸润；免疫组化显示Dysferlin呈阳性；结合其临床特点以先天性运动发育迟缓和肌酶升高为主，“CMD”临床诊断基本明确。家系trio-WES分析发现，患儿n LMNA基因上第6外显子存在一个c.1072G>A (p. E358K)杂合错义变异，该变异国内外尚未见报道(PS2);在主要人群基因频率数据库中均不存在(PM2)；该变异经多种变异预测软件预测结果均提示为有害变异(PP3)；导致编码蛋白第358位氨基酸改变，影响调控中间丝蛋白形成的Filament功能域(aa：30-386)的功能(PM1)。根据美国医学遗传学和基因组学学会(ACMG)指南，判定该新发错义变异为可能致病性变异(PS2+PM1+PM2+PP3)，可明确该患儿的基因诊断。n 结论:LMNA基因c.1072G>A (p. E358K)可能为该患儿罹患CMD的致病原因，该结果可为患儿家系的遗传咨询和产前诊断提供依据。新的n LMNA致病变异扩充了n LMNA基因的变异谱。n “,”Objective:To report on a patient with congenital muscular dystrophy (CMD) due to a missense variant of n LMNA gene and explore its pathogenicity.n Methods:The 1-year-and-1-month-old boy has presented with motor development delay and elevation of muscle enzymes for more than half a year. Congenital myopathy was suspected. Following muscle biopsy, HE staining, immunostaining and electron microscopy were conducted to clarify the clinical diagnosis. Meanwhile, DNA was extracted from the child and his parents’ peripheral venous blood samples. Trio-whole exome sequencing (trio-WES) was carried out to detect pathogenic variant in the child. Candidate variant was verified by Sanger sequencing and bioinformatic analysis.Results:Both light and electron microscopy showed a large area of necrotic muscle tissues with infiltration of inflammatory cells. Immunohistochemistry revealed a large amount of muscle cells to be diffusely positive for Dysferlin. The patient’s motor delays, elevations of muscle enzymes and histopathological results suggested a clinical diagnosis of CMD. A n de novo missense c. 1072G>A (p.E358K) variant was detected in then LMNA gene by trio-WES. The variant was unreported previously (PS2) and was absent from major allele frequency databases (PM2). It was a loss-of-function mutation and was considered as hotspot variation in the n LMNA gene (PM1) as the amino acid (E), located in position 358, was highly conserved, and change of this amino acid was found to cause destruction of the filament domain (AA: 30-386), which may result in serious damage to the intermediate filament protein. Furthermore, c. 1072G>A (p. E358K) inn LMNA gene was also predicted to be pathogenic based on MutationTaster, PROVEAN and PolyPhen-2 (PP3) analysis. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was classified to be likely pathogenic (PS2+ PM1+ PM2+ PP3).n Conclusion:The child’s condition may be attributed to the n de novo missense c. 1072G>A (p.E358K) variant of then LMNA gene. Above discovery has expanded the variant spectrum of the n LMNA gene.n