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

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.