Unleashing the Power of Multiomics: Unraveling the Molecular Landscape of Peripheral Neuropathy.

Peripheral neuropathies (PNs) affect over 20 million individuals in the United States, manifesting as a wide range of sensory, motor, and autonomic nerve symptoms. While various conditions such as diabetes, metabolic disorders, trauma, autoimmune disease, and chemotherapy-induced neurotoxicity have been linked to PN, approximately one-third of PN cases remain idiopathic, underscoring a critical gap in our understanding of these disorders. Over the years, considerable efforts have focused on unraveling the complex molecular pathways underlying PN to advance diagnosis and treatment. Traditional methods such as linkage analysis, fluorescence in situ hybridization, polymerase chain reaction, and Sanger sequencing identified initial genetic variants associated with PN. However, the establishment and application of next-generation sequencing (NGS) and, more recently, long-read/single-cell sequencing have revolutionized the field, accelerating the discovery of novel disease-causing variants and challenging previous assumptions about pathogenicity. This review traces the evolution of genomic technologies in PN research, emphasizing the pivotal role of NGS in uncovering genetic complexities. We provide a comprehensive analysis of established genomic approaches such as genome-wide association studies, targeted gene panel sequencing, and whole-exome/genome sequencing, alongside emerging multiomic technologies including RNA sequencing and proteomics. Integrating these approaches promises holistic insights into PN pathophysiology, potentially revealing new biomarkers and therapeutic targets. Furthermore, we discuss the clinical implications of genomic and multiomic integration, highlighting their potential to enhance diagnostic accuracy, prognostic assessment, and personalized treatment strategies for PN. Challenges and questions in standardizing these technologies for clinical use are raised, underscoring the need for robust guidelines to maximize their clinical utility.