Genetic Causes of Hereditary Myopathies in a Cohort of Male Patients: Molecular Diagnosis in Myopathies

Abstract

Background Hereditary myopathies are a heterogeneous group of genetic disorders affecting skeletal muscle. The molecular diagnosis of these conditions has been revolutionized by next-generation sequencing (NGS), significantly improving diagnostic accuracy. This study aimed to characterize the genetic causes of primary myopathies in a cohort of Colombian male patients. Methods A total of 175 male individuals with clinical suspicion of hereditary myopathy were evaluated. Multiplex ligation-dependent probe amplification (MLPA) was performed to detect deletions/duplications in the DMD gene, and targeted NGS panel sequencing was applied in MLPA-negative cases and those with single-exon deletions. Results MLPA identified DMD deletions or duplications in 44.6% (78/175) of patients, confirming Duchenne/Becker muscular dystrophy (DBMD). NGS was performed in 97 patients, revealing pathogenic or likely pathogenic variants in 30.4% (17/56) of the analyzed genes. The overall diagnostic yield of the combined MLPA and NGS strategy was 85.7% (150/175). DBMD was the most frequent diagnosis (74.3%; 130/175), followed by limb-girdle muscular dystrophies (5.7%; 10/175). NGS also identified 38 variants of uncertain significance (VUS) in 43.3% (42/97) of analyzed samples. Conclusions The combined use of MLPA and targeted NGS improves the molecular diagnosis of hereditary myopathies. This approach provides insights into the genetic landscape of neuromuscular disorders, enabling better clinical management, genetic counseling, and potential eligibility for emerging therapies.