Beyond Coding Variants: RNA-Level Mechanisms in Human Disease and Precision Therapeutics

Area of Science:

• Genomic Medicine
• Molecular Biology
• RNA Biology

Background:

• Clinical genomics traditionally focuses on protein-coding variations.
• Pathogenic mechanisms often involve alterations in RNA processing, stability, and surveillance.
• Previous reviews addressed RNA layers in isolation.

Purpose of the Study:

• To present an integrated framework linking RNA-level disease mechanisms to diagnostics and therapeutics.
• To provide a practical resource for clinical geneticists and translational researchers.
• To shift clinical variant interpretation towards mechanism-based, RNA-centric precision medicine.

Main Methods:

• Examination of diverse RNA-level disease mechanisms (splicing defects, PTCs, ncRNA dysregulation, etc.).
• Analysis of RNA processing, stability, localization, translation, and surveillance pathways.
• Integration of RNA sequencing, long-read transcriptomics, allele-specific expression, and functional assays.

Main Results:

• Identified distinct, mechanistically addressable disease states arising from various RNA alterations.
• Demonstrated that treatment selection should be mechanism-matched, not gene- or variant-class-based.
• Highlighted the essential role of RNA-centric analyses for diagnosis and therapeutic stratification.

Conclusions:

• A mechanism-matched framework is crucial for RNA-centric precision medicine.
• Targeted therapies (e.g., ASOs, small molecules) should align with specific RNA defects.
• Comprehensive RNA analysis is vital for accurate diagnosis and effective treatment selection.