Submission Details

The RPGR gene was first reported in relation to X-linked cases of retinitis pigmentosa in 1996 (Meindl et al., PMID: 8673101, Roepman et al., PMID: 8817343). Affected males with causal variants in RPGR have since been identified in a number of other publications, with the majority of cases showing phenotypes restricted to the eye and diagnosed with either X-linked retinitis pigmentosa 3 (PMID: 2902787, PMID: 9855162), X-linked cone-rod dystrophy 1 (PMID: 23150612, PMID: 15914600, PMID: 34800980), X-linked cone dystrophy (PMID: PMID: 33805381), or X-linked atrophic macular degeneration (PMID: 12160730). The age of onset in affected patients can range from childhood to the fourth decade of life, and presenting symptoms often include a combination of photophobia, reduced visual acuity, night blindness, electroretinogram abnormalities of both the rod and cone responses, retinal pigment epithelial abnormalities, retinal arteriolar constriction, and/or peripheral visual field loss. A small subset of cases exhibit a syndromic presentation in which retinal degeneration is accompanied by ciliary abnormalities leading to recurrent respiratory infections and hearing impairment. These cases can be diagnosed with X-linked retinitis pigmentosa and sinorespiratory infections, with or without deafness (PMID: 10094550, PMID: 12920075), or may be separately diagnosed with X-linked retinitis pigmentosa and primary ciliary dyskinesia (PMID: 16055928). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found the molecular mechanism (loss of function in the RPGR gene product) and mode of inheritance (X-linked, with female carriers ranging from unaffected to moderately or severely affected) to be consistent among unrelated patients diagnosed with either X-linked retinitis pigmentosa 3, X-linked cone-rod dystrophy 1, X-linked atrophic macular degeneration, or X-linked retinitis pigmentosa and sinorespiratory infections, with or without deafness. Despite the low intra-familiar and high inter-familiar variability in clinical features, the phenotypic variability between these diagnoses appeared to represent a spectrum of disease rather than separate disease entities. Therefore, these cases have been lumped into a single disease entity, referred to as RPGR-related retinopathy (MONDO:0100437).

Thirteen suspected deleterious variants in RPGR were scored as part of this curation (three missense, one frameshift, six nonsense, one stop-loss, and two affecting splicing), which have been collectively reported in thirteen probands in nine publications (PMID: 8673101, PMID: 16055928, PMID: 33805381, PMID: 9855162, PMID: 12160730, PMID: 34800980, PMID: 12920075, PMID: 15914600, PMID: 10094550). All probands were males and were hemizygous for the variant of interest. The mechanism of pathogenicity appears to be loss of function in the predominant retinal isoform of RPGR, characterized in some cases by nonsense, frameshift, or splicing variants predicted to trigger nonsense-mediated decay of all RPGR isoforms, which is associated with additional extraocular phenotypes (PMID: 10094550, PMID: 12920075), PMID: 16055928). One large family with co-segregation of the genotype and phenotype among affected members was scored as part of this curation, (PMID: 2902787), while other segregation evidence was not included in this curation as the maximum scoring for this evidence type had already been reached.

This gene-disease association is also supported by biochemical evidence that the RPGR protein localizes to the connecting cilia of rod and cone photoreceptors in the retina, and to the transitional zone of the motile cilia in the respiratory tract (PMID: 12766038). This indicates a possible role in regulating cytoskeletal organization and ciliary assembly. RPGR forms complexes with the ciliary proteins CEP290 (PMID: 16632484), RPGRIP1L (PMID: 33808286), and IQCB1 (PMID: 15723066), all of which are encoded by genes that harbor variants associated with inherited retinal disease. RPGR silencing in retinal pigment epithelium cells triggers shortening of the primary cilia (PMID: 20631154). Murine and canine models of RPGR loss-of-function recapitulate the inheritance pattern and retinal features of the human patients (PMID: 10725384, PMID: 11978759), while a zebrafish loss-of-function model recapitulates the ciliary defects (PMID: 19815619). The phenotypes of these models can be rescued by therapeutic administration of a human RPGR transgene (PMID: 28549772), but not by patient-associated RPGR variants (PMID: 19815619).

In summary, RPGR is definitively associated with RPGR-related retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a definitive classification. This classification has been approved by the ClinGen Retina GCEP on August 4th, 2022 (SOP Version 9).