The Role of Muscle Biopsy in the Era of Modern Genomic Medicine—A Review

This review examines the evolving role of muscle biopsy in the diagnosis of neuromuscular disorders in the era of modern genomic medicine. Historically the cornerstone of myopathy diagnosis, muscle biopsy enabled structural, histochemical, and ultrastructural characterization of muscle diseases. However, the introduction of next-generation sequencing and other genomic technologies has shifted the diagnostic paradigm, with genetic testing now serving as the preferred first-line approach for many hereditary myopathies due to its non-invasive nature and high diagnostic yield. However, muscle biopsy remains indispensable in the evaluation of inflammatory, toxic, metabolic, mitochondrial, and certain rare acquired myopathies. Biopsy is also valuable when genetic testing is inconclusive, particularly for interpreting variants of uncertain significance, through histopathological, immunohistochemical, and biochemical analyses. In certain disorders, diagnosis may rely primarily on biopsy findings. Emerging technologies, including RNA sequencing, transcriptomics, proteomics, spatial transcriptomics, and artificial intelligence-assisted pathology, are expanding the diagnostic value of muscle tissue beyond traditional morphological assessment. Rather than being replaced by genomic medicine, muscle biopsy is evolving into a complementary component of an integrated diagnostic strategy that combines clinical, pathological, and molecular data to improve diagnostic accuracy and guide precision medicine in neuromuscular disorders.