PDE6A

Inheritance Pattern: AR

Disease ID:MONDO:0700224

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0013437

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013437

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013437

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet