GRM6 was first reported in relation to autosomal recessive congenital stationary night blindness in 2005 (Dryja et al., PMID: 15781871). Congenital stationary night blindness is a clinical and genetically heterogeneous group of nonprogressive retinal disorder that can be characterized by impaired night vision, decreased visual acuity, nystagmus, myopia, and strabismus (OMIM#301500). 11 variants (variant type, e.g. missense, nonsense, frameshift) that have been reported in 5 probands in 2 publications (PMIDs: 15781871, 16249515, 26628857) that are included in this curation. Segregation data was found in 2 families (PMID:16249515, 26628857). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found the molecular mechanism and inheritance pattern (autosomal recessive) to be consistent among unrelated patients, while the phenotypic variability among them appeared to represent a spectrum of disease. Therefore, cases caused by inherited GRM6 variants have been lumped into a single disease entity, referred to as GRM6-related retinopathy (MONDO:0800397).
This gene-disease association is also supported by Grm6-deficient mouse model (PMID: 7889569). In the mammalian eye, the ON-centre and OFF-centre retinal ganglion cells form two major pathways projecting to central visual structures from the retina. Electroretinogram analysis and recordings from the superior colliculus indicated that the homozygous mutant mice showed a loss of ON responses but unchanged OFF responses to light, demonstrating that GRM6 is essential in synaptic transmission to the ON bipolar cell (PMID: 7889569). In another in vitro experiment, mutant transfected HEK293T cells demonstrated defects in protein localization when compared to wildtype (PMID:17405131). Preliminary evidence demonstrated that GRM6 gene therapy could restore vision in mice with retinal degeneration (PMID:32258214).
In summary, GRM6 is definitively associated with GRM6-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on September 1st, 2022 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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