TRPM1 was first reported in relation to autosomal recessive cases of congenital stationary night blindness type 1C by three groups in 2009 (PMIDs: 19878917, 19896109, 19896113). The hallmark CSNB phenotype is night blindness from birth or early childhood with a severely reduced or completely absent scotopic b-wave in an ERG, but normal or mildly affected a-wave. Patients also commonly present with myopia, nystagmus and/or strabismus. Because of the broad spectrum of potential phenotypes, these cases with causal variants in TRPM1 have been curated under the inclusive disease name TRPM1-related retinopathy (MONDO:0800402).
Twelve variants (four nonsense, three missense, two frameshift, and three intronic) that have been reported in eight probands in five publications (PMIDs: 35633130, 19896113, 20300565, 19896109, 19878917) are included in this curation. The mechanism of pathogenicity appears to be biallelic loss-of-function.
This gene-disease association is also supported by experimental evidence that TRPM1 exhibits its highest expression levels in retina tissue (PMID: 19878917). Additionally, expression of TRPM1 in the retina of horses with a CSNB phenotype is 0.05% of the level found in horses with normal vision (PMID: 18660533). Immunolocalization shows that TRPM1 is localized to ON bipolar cell dendrites in the outer plexiform layer (OPL) of the retina (PMID: 19896109). The ERG b-wave is absent (a defining phenotype of CSNB) in a Trpm1 (-/-) knockout mouse (PMID: 20300565). These ERG results have been replicated in another Trpm1 null mutant mouse experiment (PMID: 19861548). Furthermore, this group has also found that TRPM1 immuno-staining is absent in the OPL layer of retinal cells in Trpm1(−/−) mice. They go on to show that OKR response is reduced in knockout mice. Finally, these authors show that cell response is absent (in rod cells) or highly altered (in cone cells) in Trpm1 (-/-) mice (PMID: 19861548).
In summary, TRPM1 is definitively associated with autosomal recessive inheritance of TRPM1-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification according to the ClinGen template. This classification was approved by the ClinGen Retina GCEP on October 6, 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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