Submission Details

The PDE6A gene was first reported in relation to retinitis pigmentosa with an autosomal recessive mode of inheritance in 1995 (Huang et al., PMID: 7493036). Affected individuals with biallelic causal variants in PDE6A have since been identified in a number of subsequent publications. Phenotypes generally include a combination of early onset night blindness, reduced visual acuity, optic disc pallor, retinal blood vessel attenuation, and decreased amplitude of light-adapted and especially dark-adapted electroretinogram responses. Additional features can include bone spicule pigmentation of the retina, peripheral visual field loss, hypermetropia, and/or macular degeneration. Because of the broad spectrum of potential phenotypes, these cases with causal variants in PDE6A have been curated under the inclusive disease name PDE6A-related retinopathy.

Twelve suspected deleterious variants in PDE6A were scored as part of this curation (two nonsense and three affecting splicing), which have been collectively reported in eleven probands in five publications (PMID: 7493036, PMID: 21039428, PMID: 17110911, PMID: 30718709, PMID: 26321862). Ten probands were homozygous for the variant of interest, and six were known to be members of consanguineous families. The mechanism of pathogenicity appears to be loss of function in PDE6A, characterized in at least some cases by variants predicted to trigger the absence of the gene product. Two large families with co-segregation of the genotype and phenotype among affected members were scored as part of this curation (PMID: 21039428, PMID: 17110911), while other segregation evidence was available (PMID: 20940301) 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 expression evidence that adult retina is the human tissue type with highest levels of PDE6A mRNA (PMID: 30239781). Biochemical data similarly support a structural function in the retina by showing that PDE6A encodes a cGMP phosphodiesterase associated specifically with rod photoreceptor cells (PMID: 20940301). The PDE6A protein physically forms a complex with PDE6B and PDE6G (PMID: 227876), which are encoded by genes that harbor variants associated with retinitis pigmentosa 40 and retinitis pigmentosa 57, respectively. A canine model of biallelic Pde6a loss-of-function recapitulates features of the human patients such as visual defects, retinal blood vessel attenuation, and rod photoreceptor cell loss from the outer segment (PMID: 18775863). The development of these phenotypes can be prevented by gene therapy in the form of adeno-associated virus-mediated delivery of wild-type canine Pde6a (PMID: 28676737). Murine models of biallelic Pde6a loss-of-function similarly recapitulate human patient features and confirm the molecular defect of decreased cGMP phosphodiesterase activity in retinal tissues (PMID: 18849587). Additional experimental evidence is available in the literature (PMID: 34095146, PMID: 29212391) but has not included in this curation since the maximum scoring for this category has already been reached.

In summary, PDE6A is definitively associated with PDE6A-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 December 1st, 2022 (SOP Version 9).