Bevilacqua Jorge Alfredo, Al-Salti Abdullah Mohammed, Al Madani Abubaker, Alves da Fonseca Armando, Durmus Hacer, Chai Josiah, Alshehri Ali, Ribeiro Márcia Gonçalves, Sgobbi Paulo, Nikitin Sergey S, Vargas Steven, Furtado Adriana, Thibault Nathan, Araujo Roberto, Daba Nadia
Department of Neurology and Neurosurgery, Hospital Clínico Universidad de Chile, Santiago, Chile.
Department of Neurology, Neuroscience Center, Khoula Hospital, Muscat, Oman.
Front Genet. 2024 Nov 29;15:1477291. doi: 10.3389/fgene.2024.1477291. eCollection 2024.
Hereditary myopathies arise due to numerous pathogenic variants occurring in distinct genes, which amount to several hundred. Limb-girdle muscular dystrophies (LGMDs) constitute a heterogeneous group of neuromuscular disorders involving more than 30 genes. Clinically, LGMD is characterized by limb-girdle muscular weakness (LGMW). Late-onset Pompe disease is an important disorder with a differential diagnosis for LGMD, where next-generation sequencing (NGS) plays a crucial role in accurate and prompt diagnosis. The sensitivity and specificity of a 10-gene NGS panel have been previously evaluated for the prevalent forms of recessive LGMD (LGMD-R) and Pompe disease in Latin American patients with LGMW of unknown cause. This project aims to identify the regional relative prevalence of frequent LGMD-R subtypes and Pompe disease in a larger geographic area and to diagnose patients with LGMW by identifying genetic variants of LGMD-R and Pompe disease.
This 21-country multicentric analysis enrolled 2,372 patients with LGMW from 2017 to 2018. Sequencing analysis was performed using the Illumina NextSeq 500 system, and variant interpretation was performed according to the American College of Medical Genetics and Genomics guidelines. Pathogenic or likely pathogenic variants were seen in 11% of patients (n = 261). Among the positive cases, NGS effectively diagnosed 86.2% and 13.8% of patients with LGMD and Pompe disease, respectively. The most prevalent pathogenic acid α-glucosidase ( variant identified was c.-32-13T > G.
The study adds to the knowledge of the relative occurrence of various subtypes of LGMD worldwide. The inclusion of in the NGS panel to investigate patients with LGMW is a powerful diagnostic approach to screen for late-onset Pompe disease.
遗传性肌病是由不同基因中出现的众多致病变异引起的，这些基因多达数百个。肢带型肌营养不良症（LGMD）是一组异质性神经肌肉疾病，涉及30多个基因。临床上，LGMD的特征是肢带肌无力（LGMW）。晚发型庞贝病是一种重要的疾病，在LGMD的鉴别诊断中，下一代测序（NGS）在准确快速诊断中起着关键作用。先前已经评估了一个10基因NGS检测板对拉丁美洲原因不明的LGMW患者中隐性LGMD（LGMD-R）和庞贝病流行形式的敏感性和特异性。本项目旨在确定更大地理区域内常见LGMD-R亚型和庞贝病的区域相对患病率，并通过鉴定LGMD-R和庞贝病的基因变异来诊断LGMW患者。
这项21个国家的多中心分析在2017年至2018年期间纳入了2372例LGMW患者。使用Illumina NextSeq 500系统进行测序分析，并根据美国医学遗传学和基因组学学会的指南进行变异解读。11%的患者（n = 261）检测到致病性或可能致病性变异。在阳性病例中，NGS分别有效诊断出86.2%和13.8%的LGMD和庞贝病患者。鉴定出的最常见致病性酸性α-葡萄糖苷酶变异是c.-32-13T > G。
该研究增加了全球范围内LGMD各种亚型相对发生率的知识。在NGS检测板中纳入 以调查LGMW患者是筛查晚发型庞贝病的一种有力诊断方法。
