Submission Details

The RPE65 gene was first reported in relation to autosomal dominant cases of Retinitis pigmentosa in two apparently unrelated Irish families in 2011 (Bowne et al., PMID: 21654732). Affected individuals have since been identified in multiple other families of both Irish (PMID: 27307694) and Scottish (PMID: 29947567) descent. The disease entity exhibits incomplete penetrance, with approximately 80% of genotype-positive individuals developing the phenotype, and considerable variability in onset and severity among affected family members (PMID: 21654732, PMID: 27307694, PMID: 29947567). The disease generally presents between the second and seventh decade of life, typically with night blindness or central vision problems (PMID: 21654732, PMID: 27307694). Progression of the disease course generally reaches severe visual loss between the fifth and eighth decades of life (PMID: 27307694). Patients also exhibit other eye-specific features, including abnormalities in the light-adapted and especially the dark-adapted electroretinograms, peripheral visual field loss, chorioretinal atrophy, chorioretinal degeneration, and pigmentary retinopathy (PMID: 21654732, PMID: 27307694). Some of these choroid-specific features have led affected patients to be initially suspected for choroideremia prior to genotyping (PMID: 21654732, PMID: 29947567), and the disease entity is specifically referred to as Retinitis pigmentosa 87 with choroidal involvement. This disease entity is referred to in this curation as RPE65-related dominant retinopathy (MONDO:0100452). Additional autosomal recessive disease entities have been asserted in relation to biallelic loss-of-function variants in RPE65 (PMID: 9326941, PMID: 9326927, PMID: 9501220, PMID: 14962443, PMID: 11786058, PMID: 12960219, PMID: 15557452). While these disease entities are characterized by similar phenotypes with earlier onset, their different mode of inheritance and unique variants suggested a different mechanism of pathogenesis. Thus, RPE65 was separately curated for its relationship to those disease entities, collectively referred to as RPE65-related recessive retinopathy.

A single suspected pathogenic variant was scored as part of this curation, with observations in 5 probands (PMID: 21654732, PMID: 27307694, PMID: 29947567). While these probands represent apparently unrelated families of Irish or Scottish ancestry, at least two of the families share a wider haplotype that indicates coinheritance of a founder mutation from a distant common ancestor (PMID: 21654732). The variant encodes an Asp477Gly missense substitution within exon 13 (PMID: 21654732) and may introduce an ectopic splice site at the mRNA level that shifts the reading frame and excludes parts of exon 13 and exon 14 from the spliced RPE65 transcript (PMID: 30628748). Two of the aforementioned families had segregation evidence (PMID: 21654732) that contributed to the scoring of the gene-disease relationship. It is important to note that this variant is currently unique among known RPE65 variants in its ability to cause disease in a heterozygous state rather than a homozygous state, through an autosomal dominant mode of inheritance.

This gene-disease relationship has not been studied in case-control studies at the single variant level or aggregate variant level.

The mechanism of pathogenicity appears to be monoallelic RPE65 dysfunction, possibly characterized by the creation of an ectopic splice site that triggers a frameshift and disrupts the inclusion of the C-terminal exons 13 and 14 in the RPE65 mRNA (PMID: 30628748). Multiple reports of moderately increased mobility of the variant RPE65 gene product on gel electrophoresis (PMID: 21654732, PMID: 30628748) are consistent with this proposed effect. However, the molecular mechanism by which the variant triggers disease with a dominant mode of inheritance remains a matter of debate (PMID: 29659842, PMID: 28041994, PMID: 30628748).

This gene-disease association is also supported by experimental evidence that RPE65 expression is highly specific to the retinal pigment epithelium at both the mRNA level (PMID: 30239781) and protein level (PMID: 8474143). Biochemical studies have demonstrated that RPE65 encodes the human isomerohydrolase enzyme, a critical component of the visual retinoid cycle that regenerates 11-cis retinal following the light-induced isomerization of this pigment to all-trans retinal (PMID: 16116091). This explains why knock-in of this variant within the endogenous mouse Rpe65 locus triggers accumulation of retinal esters, electroretinogram abnormalities indicative of slower recovery of rod and cone function, and reduced retinal thickness after long-term photobleaching (PMID: 30628748). Mouse phenotypes are progressive with age and are enhanced in homozygous knock-in animals relative to their heterozygous counterparts. Two other knock-in mouse models generated by different strategies have revealed similar defects, as well as reduced levels and enhanced ubiquitination of the variant RPE65 protein, accumulation of autofluorescent spots in the fundus, and an additional defect in 11-cis-retinal regeneration (PMID: 29659842, PMID: 28041994).

In summary, the evidence of RPE65 association with RPE65-related dominant retinopathy has been demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, initially leading to a score consistent with a moderate classification. The strength of this association is further supported by the specificity of the disease phenotype and the availability of cases with whole genome sequencing data that exclude other potential disease causes within the CHM, RGR, and RHO loci. Additional unpublished cases have been submitted to ClinVar by multiple clinical testing providers (ClinVar ID: 750796). Although the single known variant associated with the disease entity is a suspected founder mutation particularly linked to families of Irish descent, the growing number of cases and confirmed absence of other linked variants from the RPE65 locus have led the expert panel to recommend an upgrade of the classification for this gene-disease relationship to Strong. Over time, a more complete understanding of the mechanism of pathogenicity of this variant and the emergence of more cases of RPE65-related dominant retinopathy in association with other variants or haplotypes are expected to further strengthen the classification of this gene-disease relationship.