Causative Variants Linked With Limb Girdle Muscular Dystrophy in an Iranian Population: 6 Novel Variants Publisher Pubmed



Mianesaz H^{1, 2} ; Ghalamkari S^{2, 3} ; Salehi M^{2, 4} ; Behnam M^{4, 5} ; Hosseinzadeh M^{2, 6} ; Basiri K^{7, 8} ; Ghasemi M^{7, 8} ; Sedghi M^{6, 7} ; Ansari B^{8, 9}
Source: Molecular Genetics and Genomic Medicine Published:2023

Abstract

Background: 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. Methods: 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. Results: 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. © 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.