Analysis of a child with congenital muscular dystrophy due to a novel variant of the LMNA gene.
10.3760/cma.j.cn511374-20201012-00711
- Author:
Wenting TANG
1
;
Ruohao WU
;
Kunyin QIU
;
Xu ZHANG
;
Zhanwen HE
Author Information
1. Department of Molecular Diagnostics, Sun Yat-sen Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China. hezhanw@mail.sysu.edu.cn.
- Publication Type:Journal Article
- MeSH:
Gene Frequency;
Genomics;
Humans;
Infant;
Lamin Type A/genetics*;
Male;
Muscular Dystrophies/genetics*;
Mutation;
Whole Exome Sequencing
- From:
Chinese Journal of Medical Genetics
2021;38(9):857-860
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To report on a patient with congenital muscular dystrophy (CMD) due to a missense variant of LMNA gene and explore its pathogenicity.
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 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).
CONCLUSION: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.
