Integrated approach to diagnosing limb-girdle muscular dystrophies in resource-limited settings

Authors

• Hammad Yousaf, Aga Khan UniversityFollow
• Lubaba Bintee Khalid, Aga Khan University
• Hijab Zahra, Aga Khan University
• Ghazala Zafar, Aga Khan UniversityFollow
• Asmat Ali, Aga Khan UniversityFollow
• Bilal Ahmad Mian, Aga Khan UniversityFollow
• Ambrin Fatima, Aga Khan UniversityFollow
• Affan Ahmed, Aga Khan UniversityFollow
• Salman Kirmani, Aga Khan UniversityFollow
• Shahid Mahmood Baig, Aga Khan UniversityFollow
• Ambrin Fatima, Aga Khan UniversityFollow
• Khairunnisa Mukhtiar, Aga Khan UniversityFollow
• Sanam Bano, Aga Khan UniversityFollow
• Mohammad Raza, Aga Khan UniversityFollow
• S. H. Ibrahim, Aga Khan UniversityFollow
• Haq Nawaz Khan, Aga Khan UniversityFollow

Document Type

Article

Department

Biological and Biomedical Sciences; Women and Child Health; Paediatrics and Child Health; Pathology and Laboratory Medicine

Abstract

Limb-girdle muscular dystrophies (LGMD) are a genetically heterogeneous group of neuromuscular disorders characterized by overlapping clinical features, including progressive muscle weakness and wasting, elevated creatine kinase (CK) levels, and motor and skeletal abnormalities. Due to phenotypic overlap and variable severity, clinical diagnosis alone is often unreliable. Incorporation of genetic investigations to aid diagnosis/differential diagnosis has accelerated the diagnostic process but remains largely limited to developed countries. Here, we employed genetic testing as a first-tier approach to simplify the diagnostic journey in a resource-limited setting, combined with preliminary functional analyses to identify the underlying genetic cause. Our cohort included 46 affected individuals (31 males, 15 females) from 29 families with a mean age of 23.59 ± 11.87 years and a mean age at onset of 14.8 ± 9.2 years. All individuals presented with progressive muscle weakness, elevated CK levels, movement difficulties, and gait abnormalities. Genetic testing identified pathogenic/likely pathogenic variants in CAPN3 (8 families), DYSF (15 families), LAMA2 (4 families), and SGCA (1 family), whereas a variant of uncertain significance was identified in COL12A1 (1 family). Preliminary functional investigations in patient-derived fibroblasts demonstrated that the COL12A1: p.(Val1051Leu) identified in Family 1 results in reduced mRNA and protein abundance. Overall, 25 unique variants were identified, including 17 novel variants. This study highlights the utility of integrating genetic and functional approaches to facilitate accurate diagnosis in low- and middle-income settings.

Comments

Pagination is not provided by author/publisher.

Publication (Name of Journal)

Human Mutation

DOI

10.1155/humu/1321391Digital Object Identifier (DOI)

Recommended Citation

Yousaf, H., Khalid, L. B., Zahra, H., Zafar, G., Ali, A., Mian, B. A., Fatima, A., Ahmed, A., Kirmani, S., Baig, S. M., Fatima, A., Mukhtiar, K., Bano, S., Raza, M., Ibrahim, S., Khan, H. N. (2026). Integrated approach to diagnosing limb-girdle muscular dystrophies in resource-limited settings. Human Mutation, 26(1).
Available at: https://ecommons.aku.edu/pakistan_fhs_mc_bbs/1133