Despite decades of progress in inherited retinal disease genetics, retinitis pigmentosa (RP) remains frustratingly under-solved: around 30–50 percent of cases still lack a definitive molecular diagnosis even after exome or genome sequencing. A new Nature Genetics study now widens the diagnostic net by implicating an unexpected class of disease-causing genes: noncoding small nuclear RNAs (snRNAs) that form the core of the spliceosome.
The study reported that heterozygous de novo and inherited dominant variants in RNU4-2 (encoding U4 snRNA) and four RNU6 paralogs (encoding U6 snRNA) cause nonsyndromic autosomal dominant RP (adRP). Across international cohorts, the team identified pathogenic variants in 153 individuals from 67 families, with recurrent “hotspot” changes clustering in a highly conserved structural region of the U4/U6 duplex.
Clinically, affected individuals presented with a classical RP phenotype, with symptom onset typically in adolescence. The cohort also showed a high frequency of associated findings that will resonate with retinal specialists: cystoid macular edema (55.9%), non-age-related lens opacities (23.6%), and vitreomacular complications (30.6%).
These newfound genetic variants could explain around 1.4% of previously undiagnosed RP cases, meaning snRNA genes deserve a place in future diagnostic pipelines – particularly for unresolved adRP and “sporadic” presentations that may reflect de novo dominant events. More broadly, the work is a reminder that the next breakthroughs in retinal genetics may lie not in new proteins, but in the noncoding architecture that keeps the transcriptome running.
