RDH12, the gene encoding retinol dehydrogenase 12, was first reported in relation to autosomal dominant retinitis pigmentosa in 2008 (Fingert et al., PMID: 18779497). RDH12-related dominant retinopathy is associated with late onset cases typically diagnosed as retinitis pigmentosa with a milder phenotype, characterized by nyctalopia and visual field loss, but relatively preserved central vision. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the difference in inheritance pattern and phenotypic variability between autosomal dominant and autosomal recessive cases led them to be split into separate disease entities. The split curation for RDH12-related recessive retinopathy has been performed separately.
This curation includes three frameshift variants that have been reported in 4 probands in 3 publications (PMIDs: 18779497, 32322264, 34031043). The score for genetic evidence is 6.5 points. The mechanism of pathogenicity is reported to be gain-of-function, most likely due to the creation of an alternate reading frame predicted to escape NMD and lead to a truncated protein with altered C-terminus.
This gene-disease association is also supported expression studies and in vitro functional assays (PMIDs: 12226107, 15865448). The RDH12 enzyme catalyzes the reduction of all-trans-retinal and its 9-cis-, 11-cis-, and 13-cis-retinal isomers in the presence of NADPH (PMID: 12226107). Human RDH12 mRNA is most highly expressed in retinal tissues (PMID: 15865448). The experimental evidence score is 1.5 points.
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Retinal Gene Curation Expert Panel on March 3rd, 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).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.