Submission Details

The REEP6 gene was first reported in relation to retinitis pigmentosa 77 with an autosomal recessive inheritance in 2016 (Arno et al., PMID: 27889058). Affected individuals with causal variants in REEP6 have since been identified in 3 other publications (PMID: 29120066, 31538292 and 33917198), with cases showing onset at ages ranging from early childhood to 39 years. Presenting phenotypes include a combination of nyctalopia, bony spicules, constricted visual fields, reduced visual acuity, attenuated retinal vessels, severe generalized retinal dystrophy with severely reduced or undetectable electroretinogram (ERG) responses and outer retinal atrophy. Additional features can include cystoid macular edema, posterior subcapsular cataracts and dyschromatopsia. These cases with causal variants in REEP6 are typically diagnosed with retinitis pigmentosa 77 (MONDO:0015013, MIM #: 617304), but have been curated under the broader disease term REEP6-related retinopathy in order to be inclusive of the full diversity of patient phenotypes.

This curation has scored ten suspected deleterious variants in REEP6 (four missense, four frameshift, one nonsense and one canonical splice site), which have been collectively reported in nine probands in four publications (PMIDs: 27889058, 29120066, 31538292 and 33917198). Most of the probands were members of consanguineous families and were homozygous for the variant of interest. The mechanism of pathogenicity appears to be loss of function in REEP6, characterized in at least some cases by variants predicted to trigger the absence of the gene product. More genetic evidence is available in the literature, but the maximum score for genetic evidence has been reached (PMID: 36819107).

This gene-disease association is also supported by expression evidence that the long isoform (REEP6.1) of REEP6 is highly expressed in the retina, specifically in rod photoreceptors (PMIDs: 34104971 and 24691551). Biochemical studies further support a structural function of REEP6 in the retina as evidenced by strong binding of NRL (associated with retinal degeneration and retinitis pigmentosa 27) in the intronic region of REEP6, which increases its promoter activity in an in vitro reporter assay (PMID: 24691551). Furthermore, REEP6 is present in a subset of clathrin-coated vesicles (STX3) and colocalizes in rod spherules. This study suggests a critical function of REEP6 in trafficking of cargo via a subset of clathrin-coated vesicles to selected membrane sites in rod photoreceptor cells (28369466). Knockdown of Reep6 in mouse retina using shRNA might lead to the death of transfected photoreceptor cells as shown by thinner outer nuclear layer in the electroporated area. Knockdown of reep6 by translation blocking morpholino in zebrafish leads to severely compromised eye development in the morphants. Taken together, these results show that REEP6 is required for retinal development in zebrafish and mouse (24691551). Reep6L135P/- compound heterozygous mice mimic the patient genotype and recapitulate the early-onset retinal degeneration phenotypes observed in the individual with retinitis pigmentosa. rAAV-mediated REEP6 transduction in photoreceptor cells successfully rescued the phenotypes including thin outer nuclear layer and rod ERG responses (PMIDs: 30101608 and 34104971).

In summary, REEP6 is definitively associated with REEP6-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 July 11th, 2024 (SOP Version 10).