Submission Details

PDE6B was first reported in relation to autosomal recessive retinitis pigmentosa (RP) in 1993 (McLaughlin et al., PMID: 8394174). In 1994, the PDE6B gene was also reported to be associated with autosomal dominant congenital stationary night blindness (CSNB) in a large Danish family referred to as the “Rambusch pedigree” (Gal et al., PMID: 8075643). Since the initial reports of PDE6B-related retinopathy, over 100 homozygous or compound heterozygous PDE6B variants have been identified in individuals and families with autosomal recessive RP (ClinVar). In some cases, carrier parents have been available for clinical evaluation and have been reported to be unaffected (PMIDs: 8394174, 7599633). In one autosomal recessive PDE6B family, the carrier parents were reported to be asymptomatic with normal fundus exam (both over age 70), however they were noted to have reduced rod electroretinograms (PMID: 25827439). To date, there is only one well-established PDE6B variant associated with autosomal dominant CSNB: c.772C>A (p.His258Asn) (PMIDs: 8075643, 17044014), which does not appear to be reported in patients with autosomal recessive RP. At least one other variant, a frameshift variant, has been reported to be associated with autosomal dominant CSNB (PMID: 24760071). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found notable differences in the inheritance pattern, phenotype, and disease variants, so autosomal recessive and autosomal dominant cases of retinopathy have been split into separate curations. This curation is for PDE6B-related recessive retinopathy, while the split curation for PDE6B-related dominant retinopathy will be performed separately.

Affected individuals with PDE6B-related autosomal recessive retinopathy typically have classic RP signs and symptoms including nyctalopia, peripheral field constriction, abnormal fundus exam (attenuated retinal vessels and bone spicules), and abnormal full-field electroretinogram. Disease onset and progression is variable, however symptom onset, particularly nyctalopia, in the first decade is often reported.

Ten variants (including missense, nonsense, frameshift, and duplication variants) that have been reported in eight probands in six publications (PMIDs: 8394174, 7599633, 18854872, 33177553, 33673512, 25827439) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function.

This gene-disease relationship is also supported by experimental evidence (e.g. animal models, expression studies, in vitro functional assays, etc.) (PMIDs: 227876, 11853768, 20940301, 26877830, 31009522, 39359097). Pde6b is expressed in the mouse retina (PMID: 26877830), and in vitro assays indicate that PDE6B forms a complex with PDE6A and PDE6G, which are both associated with retinitis pigmentosa as well (PMID: 227876). There is a naturally occurring mouse model for PDE6B-related retinitis pigmentosa. The rd1 mouse aka "rodless" has a murine viral insert in intron 1 and a second nonsense mutation in exon 7 of the Pde6b gene. Homozygous rd1 mice have retinal degeneration with rapid degeneration of rod photoreceptors and cone photoreceptor loss later (PMID: 11853768). Additional animal knockout models, such as rat, have also been created and exhibit similar retinal degeneration (PMID: 31009522). AAV2-PDE6B has been shown to restore retinal structure and function in Pde6b deficient mice (PMID: 39359097).

In summary, there is definitive evidence supporting the relationship between PDE6B and PDE6B-related recessive retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on January 2nd, 2025 (SOP Version 11).