Submission Details

PDE6G was first reported in relation to retinitis pigmentosa 57, an autosomal recessive form of retinopathy, in 2010 (Dvir et al, PMID: 20655036). This is the only disorder known to be associated with PDE6G at the current time. The disease entity has been renamed as PDE6-related retinopathy.

A canonical splice site variant shown by RT-PCR analysis to result in a frameshift has been reported in 6 homozygous affected individuals in an extended Israeli family of Muslim Arab origin (Dvir et al, 2010 PMID: 20655036). Affected individuals presented with early onset, severe disease. Two other apparently unrelated individuals have been reported (Van Schil et al, 2018, PMID: 28749477) with inherited retinal disease and homozygosity for the same copy number variant (GRCh37 chr17: g.79612525_79619171del, also denoted as NM_001290212.1(TSPAN10): c.658_NM_002602.3 (PDE6G):c.147-456del, which includes loss of coding exons 3 and 4 of PDE6G, and part of TSPAN10). Three unpublished probands and one affected sibling have been reported with retinopathy and homozygosity for the same frameshift variant, NM_002602.4:c.69dup, p.(Arg24GlnfsTer6) (Invitae, personal communication). Additional unpublished cases with homozygosity for loss of function variants are known to members of the ClinGen Retina GCEP. The cases reported in PMID: 28749477 and the unpublished cases could not be entered and scored in the GCI due to technical limitations. The disease mechanism appears to be loss of function.

This gene-disease relationship is also supported by experimental evidence. A detailed review outlines extensive evidence supporting the function of PDE6G, a function that is consistent with the disease entity (Cote et al, 2022, PMID: 34170501). In brief, PDE6G encodes the gamma (inhibitory) subunit of rod-specific phosphodiesterase 6 (PDE6). PDE6 is a multi-subunit enzyme composed of alpha and beta catalytic subunits (PDE-alpha and PDE-beta, encoded by PDE6A and PDE6B respectively), and two inhibitory gamma subunits (PDE-gamma, encoded by PDE6G). PDE6 is an essential component of the visual transduction cascade. In response to light activation, PDE6 regulates intracellular cyclic guanosine monophosphate levels by hydrolysis of cyclic guanosine monophosphate (cGMP). The PDE-gamma subunit is a multi-functional regulator of PDE6 activity, and thus plays a critical role in vision (Power et al, 2019, PMID: 31374251). PDE-gamma interacts with the products of other genes which have been implicated in retinal dystrophy, including PDE6A, PDE6B, and GNAT1 (Irwin et al, 2019, PMID: 31690623). The gene is most highly expressed in retina and retinal pigment epithelium with much lower expression in other tissues (Bryan et al, 2018, PMID: 30239781). In addition, two knock-out mouse models recapitulate the early onset, severe features of retinopathy observed in patients (Tsang et al, 1996, PMID: 8638127; Jentzsch et al, 2023, PMID: 37363133). The retinal degeneration phenotype in Pde6g knockout mice is rescued by expression of a wild type Pde6g transgene (Tsang et al, 1998, PMID: 9756475). Finally, functional alteration studies, in which different mutant Pde6g cDNAs were expressed in knockout mice, have helped to elucidate the functional domains of Pde6g and in vivo impact of different variants (Farber and Tsang, 2003, PMID: 12700134).

As noted, due to technical limitations, some cases could not be scored in the GCI. However, even if these cases were scored conservatively, the total score would exceed 12 points. Therefore, there is definitive evidence supporting the relationship between PDE6G and PDE6G-related retinopathy (also known as retinitis pigmentosa 57). This classification was approved by the ClinGen Retina Gene Curation Expert panel on June 6th, 2024 (SOP Version 10).