Hum Mutat. 2026 Oct 17;2026:1839164. doi: 10.1155/humu/1839164. eCollection 2026.
ABSTRACT
Pathogenic variants in RP2 cause X-linked RP2-associated retinopathy, a rare inherited retinal disorder typically characterized by childhood onset and progression to severe visual impairment within the first three decades of life. Despite its clinical severity, comprehensive clinical and genetic data on RP2-associated retinopathy remain limited and no therapeutic approaches have yet progressed toward clinical application. Here, we provide an overview of current molecular, clinical, and therapeutic knowledge on RP2-associated retinopathy together with an analysis of the spectrum and distribution of clinically classified, ClinVar-curated variants. Analysis of 325 ACMG/AMP Class 3-5 variants revealed that among pathogenic and likely pathogenic variants, frameshift and nonsense variants predominated, supporting loss of RP2 function as the major disease mechanism as previously described. In contrast, variants of uncertain significance were largely missense variants, underscoring the particular challenge of missense variant interpretation in RP2. Exon distribution of RP2 variants did not deviate from expectation for Class 3 variants, or for Class 4 and 5 variants in exons 2-4. However, we observed a significant enrichment of Class 4/5 variants in exon 1, driven mainly by initiator codon variants, and a depletion of Class 4/5 variants in exon 5. By integrating published knowledge on molecular mechanisms, genetic variants, clinical progression, and therapeutic development, with a detailed analysis of ClinVar-annotated RP2 variants, this narrative review outlines the current understanding of RP2-associated retinopathy and identifies key gaps that will need to be addressed for therapeutic development and clinical translation. Trial Registration: ClinicalTrials.gov: NCT06982417.
PMID:42892975 | PMC:PMC13676036 | DOI:10.1155/humu/1839164