Submission Details

The PDE6C gene was first reported in relation to cone dystrophy with an autosomal recessive mode of inheritance in 2009 (Thiadens et al., PMID: 19615668). Affected individuals with biallelic causal variants in PDE6C have since been identified in a number of subsequent publications. Phenotypes generally occur with congenital or early childhood onset and include severe color vision defects, progressive loss of visual acuity over the course of decades, reduced or absent cone/photopic ERG responses, normal rod/scotopic ERG responses, photophobia, myopia, and/or nystagmus. At least one patient has been reported with central scotoma and macular retinal pigment epithelium atrophy (PMID: 19887631). These cases with causal variants in PDE6C are specifically described as cone dystrophy 4 or achromatopsia 5 (MIM#: 613093), depending on the extent of disease progression at the time of diagnosis. Additional case reports have suggested an expanded spectrum of disease that includes phenotypes consistent with cone-rod dystrophy, including electroretinograms with decreased amplitude on both phototopic and scotopic waveforms and mild/moderate constrictions to visual field (PMID: 33001157). Because these diagnoses are considered part of the same phenotypic spectrum, this curation has evaluated a combination of cases under the disease term PDE6C-related retinopathy.

Thirteen suspected deleterious variants in PDE6C were scored as part of this curation (five nonsense, 1 frameshift, four missense, and three affecting splicing). These variants have been collectively reported in eight probands in three publications (PMID: 19615668, PMID: 19887631, PMID: 30080950). Three probands were homozygous for the variant of interest, but were not reported to be members of consanguineous families. The mechanism of pathogenicity appears to be loss of function in PDE6C, characterized in at least some cases by variants predicted to trigger the absence of the gene product or loss of the majority of its enzymatic activity. Additional genetic evidence was available (PMID: 32306724, PMID: 33001157, PMID: 37433860) but 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 evidence that PDE6C is highly expressed specifically in retinal tissues (PMID: 30239781). Biochemical data show that PDE6C encodes a cGMP phosphodiesterase that is part of the phototransduction cascade and is associated specifically with cone photoreceptor cells, consistent with the cone-specific dysfunction observed in the human patients (PMID: 19801642). This biochemical function parallels that of the PDE6A gene, which encodes a rod-specific cGMP phosphodiesterase and harbors loss-of-function variants associated with retinal dystrophy (PMID: 7493036). Naturally occurring zebrafish, mice, and rhesus macaque models harboring biallelic loss-of-function variants in the gene orthologous to PDE6C recapitulate many of the features of the human patients such as reduced visual acuity, particularly under normal lighting conditions, lack of light-adapted ERG responses, and normal dark-adapted ERG responses (PMID: 18824093, PMID: 19887631, PMID: 30667376). These models also collectively exhibit progressive thinning of the outer nuclear layer and photoreceptor outer segments within the macula, caused by rapid and progressive loss of cone photoreceptors (PMID: 18824093, PMID: 19887631, PMID: 30667376).

In summary, PDE6C is definitively associated with PDE6C-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 November 2nd, 2023 (SOP Version 10).