Tang Wenting, Wu Ruohao, Qiu Kunyin, Zhang Xu, He Zhanwen
Department of Molecular Diagnostics, Sun Yat-sen Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2021 Sep 10;38(9):857-860. doi: 10.3760/cma.j.cn511374-20201012-00711.
To report on a patient with congenital muscular dystrophy (CMD) due to a missense variant of LMNA gene and explore its pathogenicity.
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.
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 de novo missense c.1072G>A (p.E358K) variant was detected in the 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 variant and was considered as hotspot variant in the 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) in 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).
The child's condition may be attributed to the de novo missense c.1072 G>A (p.E358K) variant of the LMNA gene. Above discovery has expanded the variant spectrum of the LMNA gene.
报告1例因LMNA基因错义变异导致的先天性肌营养不良（CMD）患者，并探讨其致病性。
该1岁1个月男童出现运动发育迟缓及肌酶升高半年余，怀疑为先天性肌病。进行肌肉活检后，行苏木精-伊红（HE）染色、免疫染色及电子显微镜检查以明确临床诊断。同时，提取患儿及其父母外周静脉血样本的DNA，采用三联体全外显子测序（trio-WES）检测患儿的致病变异。候选变异通过桑格测序和生物信息学分析进行验证。
光镜和电镜均显示大片坏死的肌肉组织伴有炎性细胞浸润。免疫组化显示大量肌细胞Dysferlin弥漫性阳性。患者的运动发育迟缓、肌酶升高及组织病理学结果提示临床诊断为CMD。通过trio-WES在LMNA基因中检测到一个新发的错义变异c.1072G>A（p.E358K）。该变异此前未被报道（PS2），且在主要等位基因频率数据库中未出现（PM2）。它是一个功能缺失变异，并被认为是LMNA基因中的热点变异（PM1），因为位于358位的氨基酸（E）高度保守，且发现该氨基酸的改变会导致丝状结构域（氨基酸：30 - 386）的破坏，这可能会对中间丝蛋白造成严重损害。此外，基于MutationTaster、PROVEAN和PolyPhen-2（PP3）分析，LMNA基因中的c.1072G>A（p.E358K）也被预测为致病。根据美国医学遗传学与基因组学学会（ACMG）的指南，该变异被分类为可能致病（PS2+PM1+PM2+PP3）。
患儿的病情可能归因于LMNA基因的新发错义变异c.1072G>A（p.E358K）。上述发现扩展了LMNA基因的变异谱。
