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ORIGINAL RESEARCH article

Front. Genet.
Sec. Genetics of Common and Rare Diseases
Volume 15 - 2024 | doi: 10.3389/fgene.2024.1477291

Detection of Gene Variants Associated with Recessive Limb-Girdle Muscular Weakness and Pompe Disease in a Global Cohort of Patients Through the Application of Next-Generation

Provisionally accepted
Jorge Alfredo Bevilacqua Jorge Alfredo Bevilacqua 1*Abdullah Mohammed Al-Salti Abdullah Mohammed Al-Salti 2Abubaker Al Madani Abubaker Al Madani 3Armando Alves Da Fonseca Armando Alves Da Fonseca 4Hacer Durmus Hacer Durmus 5Josiah Chai Josiah Chai 6Ali Alshehri Ali Alshehri 7Márcia Gonçalves Ribeiro Márcia Gonçalves Ribeiro 8Paulo Sgobbi Paulo Sgobbi 9Sergey S Nikitin Sergey S Nikitin 10Steven Vargas Steven Vargas 11Adriana Furtado Adriana Furtado 12Nathan Thibault Nathan Thibault 13Roberto Araujo Roberto Araujo 13Nadia Daba Nadia Daba 13
  • 1 Hospital Clínico Universidad de Chile, Santiago, Chile
  • 2 Neuroscience Center, Khoula Hospital, Muscat, Oman
  • 3 Mohammed Bin Rashid University, Rashid Hospital, Dubai, United Arab Emirates
  • 4 DLE Laboratory, Rio de Janeiro, Brazil
  • 5 Faculty of Medicine, Istanbul University, Istanbul, Istanbul, Türkiye
  • 6 National Neuroscience Institute (TTSH Campus), Singapore, Singapore
  • 7 King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
  • 8 Medical Consulting Sector of Personalized Medicine, DLE Laboratory, Rio de Janeiro, Brazil
  • 9 Federal University of São Paulo, São Paulo, São Paulo, Brazil
  • 10 Research Centre for Medical Genetics, Moscow, Moscow Oblast, Russia
  • 11 Manuel Velasco Suárez National Institute of Neurology and Neurosurgery, Mexico City, México, Mexico
  • 12 Sanofi, São Paulo, Brazil
  • 13 Sanofi, Cambridge, United States

The final, formatted version of the article will be published soon.

    Introduction: 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 nextgeneration 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 2372 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 withLGMD and Pompe disease, respectively. The most prevalent pathogenic acid α-glucosidase (GAA) variant identified was c.-32-13T>G.The study adds to the knowledge of the relative occurrence of various subtypes ofLGMD worldwide. The inclusion of GAA in the NGS panel to investigate patients with LGMW is a powerful diagnostic approach to screen for late-onset Pompe disease.

    Keywords: Next-generation sequencing, Late-onset Pompe disease, Limb-girdle muscular dystrophies, Limb-girdle muscular weakness, acid α-glucosidase

    Received: 07 Aug 2024; Accepted: 12 Nov 2024.

    Copyright: © 2024 Bevilacqua, Al-Salti, Al Madani, Alves Da Fonseca, Durmus, Chai, Alshehri, Ribeiro, Sgobbi, Nikitin, Vargas, Furtado, Thibault, Araujo and Daba. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jorge Alfredo Bevilacqua, Hospital Clínico Universidad de Chile, Santiago, Chile

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