Submission Details

The RP9 gene was first reported in relation to autosomal dominant retinitis pigmentosa (RP) in 1992 (Jay et al., PMID:1479605). RP is a genetically heterogeneous disease with multiple genetic loci implicated in the disease. It is the most common group of inherited retinal disorders that progress from night blindness to mid-peripheral vision loss (tunnel vision), followed by central vision loss, and eventual blindness. Clinical phenotypes include classic fundus appearance with “bone spicules”, cystoid macular edema, narrowed vasculature, waxy pallor of optic disk, and diminished or undetectable electroretinography responses. Nine variants (missense, nonsense, frameshift, intronic) that have been reported in nine probands in nine publications (PMID: 1479605, 12032732, 33090715, 33576794, 29785639, 33946315, 31736247, 24938718, 32100970) were considered for curation. Three variants were not scored due to high allele frequencies (maximum credible population AF was set at 3.33e-05, calculated using https://cardiodb.org/allelefrequencyapp/). The remaining six variants scored were: c.44C>T (p.Ala15Val), c.436C>T (p.Arg146Ter), c.448C>T (p.Arg150Ter), c.380A>G (p.Asn127Ser), c.410A>T (p.His137Leu), and RP9: c.511_512delGA (p.Glu171Argfs*2). The literature consisted of one segregation study of a multigenerational family from the United Kingdom by Jay et al. and others (PMID: 1479605, 8025041, 8513323). This study is the original report that mapped RP to the RP9 locus, and identified the His137Leu variant. Whether His137Leu is the causative variant for the phenotype has been questioned (PMID: 16799052) due to the presence of a distally located highly identical copy of RP9, complicating mutation detection and interpretation. The remaining curated variants lacked case-level or co-segregation information as they were identified in screening studies of large RP cohorts. The available evidence suggests the mechanism of pathogenicity is dominant negative. This gene-disease association is supported by experimental evidence from in vitro and in vivo functional assays, and expression studies (PMID: 30239781, 15474994, 28216641, 15541726). Maita et al. (PMID: 15541726, 15474994) reported RP9 is a splicing factor that associates with the spliceosome. Lv et al. (PMID: 28216641) used the CRISPR-CAS method to show that knock-out and knock-in of His137Leu mutation decreased cell proliferation and migration in a mouse retinal cell line. In summary, RP9 lacks strong genetic and functional evidence, and its calculated association with autosomal dominant retinitis pigmentosa is LIMITED. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on February 6, 2025 (SOP Version 10).