{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T15:13:59Z","timestamp":1783610039273,"version":"3.55.0"},"reference-count":134,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Clinical genomics has traditionally focused on protein-coding variation, yet many pathogenic mechanisms arise through alterations in RNA processing, stability, localisation, translation, and surveillance. Prior reviews have addressed individual RNA layers, splicing, non-coding RNAs, RNA therapeutics, or RNA diagnostics in isolation. This review presents an integrated, mechanism-matched framework linking RNA-level disease mechanisms to diagnostic reasoning and therapeutic selection across all major RNA layers, offering a practical resource for clinical geneticists and translational researchers. I examine how splicing defects, pseudoexon inclusion, polyadenylation disruption, RNA editing loss, untranslated-region variants, premature termination codons, stop-loss variants, RNA-binding protein dysfunction, non-coding RNA dysregulation, altered codon usage, ribosome stalling, and surveillance pathway failure, including nonsense-mediated decay, nonstop decay, and no-go decay, each create distinct and mechanistically addressable disease states. A central argument of this review is that treatment selection must be mechanism-matched rather than gene- or variant-class-based: splice defects may require antisense oligonucleotide (ASO)-mediated correction or small-molecule splice modulation; toxic transcripts may require ASO- or siRNA-mediated silencing; haploinsufficiency may require mRNA replacement or transcript rescue; premature termination codons are candidates for readthrough only when transcript and protein context are favourable. I further argue that RNA sequencing, long-read transcriptomics, allele-specific expression analysis, and functional assays are essential for both diagnosis and therapeutic stratification. The framework described here moves clinical variant interpretation beyond descriptive classification toward mechanism-based, RNA-centric precision medicine.<\/jats:p>","DOI":"10.3390\/genes17070777","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:06:34Z","timestamp":1782875194000},"page":"777","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond Coding Variants: RNA-Level Mechanisms in Human Disease and Precision Therapeutics"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6448-6618","authenticated-orcid":false,"given":"Himanshu","family":"Goel","sequence":"first","affiliation":[{"name":"Hunter Genetics, P.O. Box 84, Waratah, Newcastle, NSW 2298, Australia"},{"name":"School of Medicine and Public Health, University of Newcastle, Callaghan, Newcastle, NSW 2308, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1038\/s41467-026-68284-9","article-title":"De novo variants in the splicing factor gene SF3B1 are associated with neurodevelopmental disorders","volume":"17","author":"Uguen","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Liu, Q., Fang, L., and Wu, C. (2022). Alternative Splicing and Isoforms: From Mechanisms to Diseases. Genes, 13.","DOI":"10.3390\/genes13030401"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Goel, H., and Goel, A. (2024). MicroRNA and Rare Human Diseases. 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