Department of Human Genetics, Medical School, University of Debrecen, Debrecen, Hungary.
Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran.
Mol Genet Genomic Med. 2023 Feb;11(2):e2101. doi: 10.1002/mgg3.2101. Epub 2022 Nov 14.
Limb-girdle muscular dystrophy (LGMD) is a non-syndromic muscular dystrophy caused by variations in the genes involved in muscle structure, function and repair. The heterogeneity in the severity, progression, age of onset, and causative genes makes next-generation sequencing (NGS) a necessary approach for the proper diagnosis of LGMD.
In this article, 26 Iranian patients with LGMD criteria were diagnosed with disease variants in the genes encoding calpain3, dysferlin, sarcoglycans and Laminin α-2. Patients were referred to the hospital with variable distribution of muscle wasting and progressive weakness in the body. The symptoms along with biochemical and EMG tests were suggestive of LGMD; thus the genomic DNA of patients were investigated by whole-exome sequencing including flanking intronic regions. The target genes were explored for the disease-causing variants. Moreover, the consequence of the amino acid alterations on proteins' secondary structure and function was investigated for a better understanding of the pathogenicity of variants. Variants were sorted based on the genomic region, type and clinical significance.
In a comprehensive investigation of previous clinical records, 6 variations were determined as novel, including c.1354-2 A > T and c.3169_3172dupCGGC in DYSF, c.568 G > T in SGCD, c.7243 C > T, c.8662_8663 insT and c. 4397G > C in LAMA2. Some of the detected variants were located in functional domains and/or near to the post-translational modification sites, altering or removing highly conserved regions of amino acid sequence.
肢带型肌营养不良症（LGMD）是一种非综合征性肌营养不良症，由涉及肌肉结构、功能和修复的基因变异引起。严重程度、进展、发病年龄和致病基因的异质性使得下一代测序（NGS）成为 LGMD 正确诊断的必要方法。
在本文中，26 名符合 LGMD 标准的伊朗患者被诊断出编码钙蛋白酶 3、肌营养不良蛋白、 sarcoglycans 和层粘连蛋白 α-2 的基因中有疾病变异。患者因肌肉萎缩和身体进行性无力而被送往医院就诊。症状以及生化和 EMG 测试均提示为 LGMD；因此对患者的基因组 DNA 进行了全外显子测序，包括侧翼内含子区域。对目标基因进行了探索，以确定致病变异。此外，还研究了氨基酸改变对蛋白质二级结构和功能的影响，以便更好地了解变异的致病性。根据基因组区域、类型和临床意义对变异进行了分类。
在对以往临床记录的全面调查中，确定了 6 种新的变异，包括 DYSF 中的 c.1354-2 A>G>T 和 c.3169_3172dupCGGC、SGCD 中的 c.568>G>T、c.7243 C>T、c.8662_8663 insT 和 LAMA2 中的 c.4397G>C。一些检测到的变异位于功能域内或靠近翻译后修饰位点，改变或去除了氨基酸序列的高度保守区域。
