Submission Details

The PRPH2 gene was first reported in relation to autosomal dominant retinitis pigmentosa in 1991 (PMID: 1749427, PMID: 1684223). Subsequent publications expanded the phenotypic spectrum associated with heterozygous PRPH2 variants to include diverse diagnoses such as central areolar choroidal dystrophy 2 (PMID: 7493155), patterned macular dystrophy 1 (PMID: 8485574), vitelliform macular dystrophy 3 (PMID: 9338584), retinitis punctata albescens (PMID: 8485575), and Stargardt macular dystrophy (PMID: 8111389). These cases collectively exhibit a wide variety of ophthalmic features ranging from nyctalopia, reduced visual acuity, and decreased light- and dark-adapted electroretinogram (ERG) amplitudes to choroidal neovascularization, macular pattern dystrophy, and/or yellow deposits at the level of the retinal pigment epithelium. The spectrum of disease also includes cases with biallelic PRPH2 variants diagnosed as Leber congenital amaurosis 18 (PMID: 26061163) or juvenile retinitis pigmentosa (PMID: 23847139). These biallelic cases exhibit earlier onset and phenotypes such as reduced visual acuity, undetectable ERG responses, nystagmus, attenuation of retinal blood vessels, reduced macular thickness, patchy atrophy of the retinal pigment epithelium, and subretinal deposits. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (PRPH2 loss of function) was found to be consistent among dominant and recessive cases of retinitis pigmentosa 7 (MIM#: 608133), central areolar choroidal dystrophy 2 (MIM#: 13105), patterned macular dystrophy 1 (MIM#: 169150), vitelliform macular dystrophy 3 (MIM#: 608161), retinitis punctata albescens (MIM#: 136880), and Leber congenital amaurosis (MIM#: 608133). The phenotypic variability between these diagnoses appears to represent a spectrum of disease rather than separate disease entities, with some families including affected individuals receiving different diagnoses and/or exhibiting different modes of inheritance (PMID: 26061163, PMID: 31618092). Therefore, cases carrying disease-causing PRPH2 variants have been lumped into a single disease entity, referred to as PRPH2-related retinopathy, with a semidominant mode of inheritance.

Eight suspected disease-causing variants were scored as part of this curation (one nonsense, three frameshift, three missense, and one short in-frame deletion); these have been collectively reported in nine probands in seven publications (PMID: 1749427, PMID: 1684223, PMID: 8485575, PMID: 8485576, PMID: 8251014, PMID: 7710395, PMID: 8111389, PMID: 26061163, PMID: 23847139). Five of the probands scored in this curation carried single heterozygous disease-associated variants within the PRPH2 locus, while the other two probands carried biallelic PRPH2 disease-associated variants. The molecular mechanism appears to include PRPH2 haploinsufficiency and biallelic loss of PRPH2 function (conferred by null and/or hypomorphic variants). It is not yet clear whether this loss-of-function mechanism is shared by all disease-causing variants and mouse studies suggest that some heterozygous missense variants may have dominant negative effects (PMID: 11978760, PMID: 15254014, PMID: 25167981, PMID: 35344225). Interestingly, some variants such as the c.554T>C (p.Leu185Pro) change appear to be associated with incomplete penetrance in the heterozygous state, and many of the heterozygous carriers from families with biallelic cases appear to be sub-clinically affected (PMID: 23847139). It is noted that the variant has also been observed in affected individuals believed to be linked to a digenic mode of inheritance, when it is encountered in heterozygous state together with a heterozygous presumed loss-of-function variant in the ROM1 gene (PMID: 8202715). However, these cases have not been considered in the present curation. Two families with segregation evidence contributed to the scoring of the gene-disease relationship (PMID: 1749427, PMID: 1684223). The literature included more case-level and co-segregation evidence, but its inclusion in this curation was not necessary to reach the maximum score for genetic evidence.

This gene-disease association is also supported by experimental evidence indicating that dysgenesis of the photoreceptor outer segment discs may be the shared defect underlying PRPH2-related disease. PRPH2 is specifically expressed in retinal tissues (PMID: 30239781) and the protein product localizes particularly to the retinal outer segments (PMID: 1992463). Wild-type Prph2 expression in the developing mouse retina begins on day postnatal day 6, coinciding with the formation of the photoreceptor outer segment discs, and is consistent with the idea that PRPH2 functions as an adhesion molecule that stabilizes these structures. PRPH2 protein physically interacts and forms a complex with the protein product of the ROM1 gene (PMID: 8202715). PRPH2 and ROM1 co-localize within the rim regions of outer segment discs in the mouse retina (PMID: 25001182). A naturally occurring mouse model with homozygous loss-of-function variants within the Prph2 locus shows progressive degeneration of the retina, absence of rods (PMID: 705766, PMID: 419532), abnormal development of photoreceptor outer segments, gradual photoreceptor degeneration (PMID: 2918924), and ERG recordings with completely extinguished responses (PMID: 6483282). A second mouse model with a heterozygous knock-in of the c.422A>G (p.Tyr141Cys) variant into the Prph2 locus recapitulates human patient features such as photoreceptor outer segment loss, decreased rod ERG response, yellow retinal flecks in the fundus and abnormal high molecular weight complexes containing Prph2 (PMID: 25001182).

In summary, PRPH2 is definitively associated with PRPH2-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 was approved by the ClinGen Retina Gene Curation Expert Panel on February 1st, 2024 (SOP Version 10).