Submission Details

RGS9 gene was first reported in relation to autosomal recessive Bradyopsia in 2004 (Nishiguchi et al., 2004). Bradyopsia was reported to be characterized by difficulty in adjusting to changes in luminance, difficulty in seeing moving objects, and normal to subnormal visual acuity. Routine electroretinograms showed normal responses to scotopic stimulus flashes but responses to standard high-density flashes were strikingly reduced in amplitude. At least 03 patients were evaluated for neurologic features and were found to be normal. Color vision was normal in all patients while fundus appeared normal in most of the cases except slight pigment alterations in the maculae of one patient. The ophthalmic clinical features in patients were found to be non-progressive (PMIDs: 17826834, 19818506).
By far, one missense and one nonsense variant have been reported in 05 human subjects (PMIDs: 14702087, 19818506). Four (2 siblings and 2 unrelated) Dutch patients were found to be homozygous for p.Trp299Arg variant while their unaffected parents were heterozygous for this variant. One British male was compound heterozygous for p.Trp299Arg and p.Arg128Ter (PMID: 19818506). The mechanism of pathogenicity is reported to be loss of function. This gene-disease association is also supported by animal models, expression studies and in vitro assays (PMIDs: 10676965, 25257059, 10564809, 14702087). It was reported in an expression study that there are two protein isoforms of RGS9, a retina specific RGS9-1, and a brain specific RGS9-2. The reported variants seem to affect both isoforms of RGS9 however no neurological features were reported in any patients. A single-turn over transducin GTPase assay demonstrated that activity of transducin protein is reduced with the use of mutant RGS9 domains as compared to the wild type RGS9. Furthermore, in a RGS9 knock out study, the null mice showed slow recovery of photoresponse on electroretinogram as compared to the control mice (PMID: 10676965). In another RGS9 knockout study, the null mice showed delayed pupillary reflex as well as photophobia (PMID: 25257059). Both mouse knockout studies seem to recapitulate the phenotype observed in human subjects. In a co-immunoprecipitation study RGS9 was identified in a heterotetrameric complex containing RGS9-1, G5L, G_Beta5L and R9AP (RGS9BP), R9AP interacts with the N-terminal domain of RGS9-1. Mutations in R9AP has been reported to cause autosomal recessive Bradyopsia (PMIDs: 14702087, 19818506). In summary, there is moderate evidence to support the relationship between RGS9 and autosomal recessive Bradyopsia. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. The classification was approved by the ClinGen Retina GCEP on September 8th, 2021.