The Molecular Diagnosis of Myopathies: Integrating Genomic, Proteomic, and Pathological Insights Toward Precision Medicine

Genetic myopathies encompass a heterogeneous spectrum of neuromuscular disorders whose diagnosis remains challenging despite major technological advances. Traditional methods such as clinical evaluation, creatine kinase measurement, electromyography, and muscle histopathology remain valuable tools for recognizing disease patterns and, when clinically indicated, for complementing and guiding molecular investigations. However, genetically complex or atypical cases still lack an appropriate approach for assertive diagnosis. Aiming to shed light on emerging integrative molecular approaches, this review will discuss the evolving diagnostic landscape of myopathies, highlighting the integration of next-generation molecular tools with conventional methodologies for assertive diagnosis. Long-read sequencing and optical genome mapping have markedly increased diagnostic yield by enabling comprehensive detection of structural variants and complex genomic rearrangements in different myopathies. Complementary proteomic and transcriptomic analyses provide functional insight into how genetic variants alter protein expression and cellular pathways, supporting biomarker discovery and therapeutic development. Together, these omics approaches bridge the gap between genetic alterations and their functional and clinical manifestations in myopathies. They improve the interpretation of variants of uncertain significance, facilitate the identification of biomarkers linked with disease severity or therapeutic response, and support the development of personalized therapeutic strategies, advancing precision medicine in neuromuscular disorders.