Submission Details

The PROM1 gene was first reported in relation to autosomal recessive retinal degeneration in 2000 (PMID: 10587575). Subsequent publications expanded the phenotypic spectrum associated with homozygous or compound heterozygous PROM1 variants to include diverse diagnoses such as retinitis pigmentosa 41 (PMID: 17605048) and cone-rod dystrophy 12 (PMID: 24474277). These cases typically have onset in childhood or adolescence and exhibit a wide variety of retinal features ranging from macular degeneration, progressive reduction in visual acuity, and central scotoma to night blindness, peripheral visual field loss, retinal blood vessel attenuation, and optic disc pallor. Electroretinogram responses are generally decreased in amplitude or undetectable, particularly from cones. Degeneration of the retinal pigment epithelium in the macula is often observed and may be described as bull’s eye maculopathy. Optical coherence tomography images generally show retinal thinning and particularly loss of the photoreceptor layer. The spectrum of disease also includes cases with heterozygous PROM1 variants diagnosed as cone-rod dystrophy 12 (PMID: 35947379), Stargardt-like macular dystrophy (PMID: 29416601), or retinal macular dystrophy type 2 (PMID: 18654668). These heterozygous cases exhibit relatively later onset but a similar range of phenotypes that can include reduced visual acuity, bull's-eye macular dystrophy, progressive macular atrophy, color vision abnormalities, and night blindness. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, recessive cases of cone-rod dystrophy or retinitis pigmentosa were compared with dominant cases of cone-rod dystrophy, retinal macular dystrophy, or Stargardt-like maculopathy. The shared mode of inheritance, molecular mechanism (biallelic loss-of-function) and phenotypic overlap among recessive cases motivated cone-rod dystrophy 12 and retinitis pigmentosa 41 to be combined into a single gene curation, with the lumped disease entity referred to as PROM1-related recessive retinopathy. On the other hand, cases with overlapping phenotypes but a dominant mode of inheritance differed in their molecular mechanism (dominant negative), whereas the recessive families had unaffected heterozygous carriers. Therefore, dominant cases have been lumped into a separate disease entity, referred to as PROM1-related dominant retinopathy.

Eight suspected disease-causing variants were scored as part of this curation (three nonsense, three frameshift, one canonical splice site variant, and one non-canonical intronic variant disrupting splicing), which have been collectively reported in six probands in six publications (PMID: 10587575, PMID: 17605048, PMID: 24474277, PMID: 24763286, PMID: 25472526, PMID: 26702251). Four of the probands scored in this curation harbored the variant in the homozygous state, with three reported as consanguineous, while two other probands harbored variants in compound heterozygosity. Two large families with evidence of co-segregation of the genotype with affected status contributed to the scoring of the gene-disease relationship (PMID: 10587575, PMID: 17605048). 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 degeneration of the photoreceptor layer may be the shared defect underlying PROM1-related recessive disease. PROM1 is specifically expressed in retinal tissues (PMID: 30239781) and the protein product localizes particularly to the discs at the base of the photoreceptor cell outer segments (PMID: 10587575, PMID: 18654668). This localization is consistent with the known association of PROM1 with membrane protrusions in general (PMID: 10681530) and its proposed function as an organizer of cell membrane topology in the morphogenesis of the developing photoreceptor cell outer segment disc membrane. The CDHR1 gene product similarly localizes to these structures, co-immunoprecipitates with PROM1 (PMID: 18654668), and harbors variants associated with cone-rod dystrophy 15 (PMID: 20805371), retinal macular dystrophy (PMID: 28765526), and retinitis pigmentosa 65 (PMID: 20087419). Homozygous knockout of the mouse ortholog Prom1 results in light-dependent degeneration of the photoreceptor and outer nuclear layers, and defective dark-adapted electroretinogram responses (PMID: 25414197). Homozygous deletion of the zebrafish ortholog Prom1b results in photoreceptor degeneration, enhanced apoptosis, loss of the outer nuclear layer, and delayed morphogenesis of outer segment discs (PMID: 31362982).

In summary, PROM1 is definitively associated with PROM1-related recessive 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 April 4th, 2024 (SOP Version 10).