RDH12, Retinol Dehydrogenase 12, was first reported in relation to RDH12-related recessive retinopathy in patient described with Leber congenital amaurosis, LCA, in 2004 (Janeke et al., PMID: 15258582). Variants in RDH12 cause early-onset retinal degeneration leading to vision loss with variable severity. To capture the overlapping spectrum of clinical presentations linked to this gene, it is curated under the disease entity “inherited retinal degeneration”. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found there to be a difference in inheritance pattern phenotypic variability. Therefore, the curation will be split into autosomal recessive inherited retinal degeneration, which includes cases described with autosomal recessive LCA (OMIM: 612712) and autosomal dominant inherited retinal degeneration, which will include autosomal dominant retinitis pigmentosa (OMIM: 268000). The split curation for autosomal dominant condition will be curated separately. Fifteen variants (12 missense, 2 nonsense, 1 frameshift) that have been reported in 11 probands in 2 publications (PMIDs: 15258582, 32014858) are included in this curation. [Additional essential genetic evidence description]. 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 LOF. This gene-disease association is also supported animal models, expression studies and in vitro functional assays (PMIDs: 12226107, 16269441, 17032653). Haesseler et al (12226107) demonstrates that RDH12 enzyme catalyzed the reduction of all-trans-retinal and its 9-cis-, 11-cis-, and 13-cis-retinal isomers in the presence of NADPH. While Thompson et al. (16269441) shows expression of the transcript localizes to the inner segments of rod and cone photoreceptors. Genetic alterations in RDH12 result in significantly decreased enzymatic activity and reduced expression of the protein suggesting LOF. Finally, animal models show photoreceptor degeneration in RDH12 knockouts. In summary, there is definitive evidence to support the relationship between RDH12 and RDH12-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 Retinal GCEP on the meeting date March 3, 2022 (SOP Version 8).
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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