Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Nov 29:15:1477291.
doi: 10.3389/fgene.2024.1477291. eCollection 2024.

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 sequencing analysis

Jorge Alfredo Bevilacqua  1 , Abdullah Mohammed Al-Salti  2 , Abubaker Al Madani  3 , Armando Alves da Fonseca  4 , Hacer Durmus  5 , Josiah Chai  6 , Ali Alshehri  7 , Márcia Gonçalves Ribeiro  8 , Paulo Sgobbi  9 , Sergey S Nikitin  10 , Steven Vargas  11 , Adriana Furtado  12 , Nathan Thibault  13 , Roberto Araujo  14 , Nadia Daba  13
Affiliations

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 sequencing analysis

Jorge Alfredo Bevilacqua et al. Front Genet. .

Abstract

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 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.

Methods and results: 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 (GAA) variant identified was c.-32-13T > G.

Conclusion: The study adds to the knowledge of the relative occurrence of various subtypes of LGMD 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: acid α-glucosidase; late-onset Pompe disease; limb-girdle muscular dystrophies; limb-girdle muscular weakness; next-generation sequencing.

PubMed Disclaimer

Conflict of interest statement

JAB, AMA, AAM, AAF, HD, JC, AA, PS, SSN, SV, and RA have received advisory board honoraria from Sanofi. JAB has received travel support and lecture and speaker honoraria from Sanofi. MGR has nothing to disclose. AF, RA, NT, and ND are employees of Sanofi and hold shares and stock options. The funder had the following involvement in the study: logistic support and editorial assistance for the development of this manuscript.

Figures

FIGURE 1
FIGURE 1
Frequency of individuals with confirmed LGMD-R subtype and Pompe disease (N = 261) Abbreviations: LGMD: Limb–girdle muscular dystrophy; LGMD-R: Recessive limb–girdle muscular dystrophy.
See this image and copyright information in PMC

References

    1. Benarroch L., Bonne G., Rivier F., Hamroun D. (2020). The 2021 version of the gene table of neuromuscular disorders (nuclear genome). Neuromuscul. Disord. 30, 1008–1048. 10.1016/j.nmd.2020.11.009 - DOI - PubMed
    1. Benarroch L., Bonne G., Rivier F., Hamroun D. (2024). The 2024 version of the gene table of neuromuscular disorders (nuclear genome). Neuromuscul. Disord. 34, 126–170. 10.1016/j.nmd.2023.12.007 - DOI - PubMed
    1. Bevilacqua J. A., Guecaimburu Ehuletche M. D. R., Perna A., Dubrovsky A., Franca M. C., Vargas S., et al. (2020). The Latin American experience with a next generation sequencing genetic panel for recessive limb-girdle muscular weakness and Pompe disease. Orphanet J. Rare Dis. 15, 11. 10.1186/s13023-019-1291-2 - DOI - PMC - PubMed
    1. Cerino M., González-Hormazábal P., Abaji M., Courrier S., Puppo F., Mathieu Y., et al. (2022). Genetic profile of patients with limb-girdle muscle weakness in the Chilean population. Genes 13, 1076. 10.3390/genes13061076 - DOI - PMC - PubMed
    1. Ellard S., Baple E. L., Callaway A., Berry I., Forrester N., Turnbull C., et al. (2020). ACGS best Practice Guidelines for variant classification in rare disease 2020. Available at: https://www.acgs.uk.com/media/11631/uk-practice-guidelines-for-variant-c... (Accessed June 21, 2021).

LinkOut - more resources