Researchers based at the Institute of Ophthalmology, University College London, have identified a rare gene variant within RDH12, encoded by the retinal dehydrogenase enzyme functioning for the retinoid cycle. The novel RDH12 heterozygous variant (RDH12, c.763delG) has been associated with a rod-cone dystrophy with variable expression. The RDH12 finding of the research is predicted to result a dominant heterozygous gain-of-function outcome, usually classified by autosomal recessive (LCA13). If correct, an anti-sense oligonucleotide strategy could be used to take out the dominant gain-of-function allele leaving with at least 50% of normal RDH12.
RDH12 is a gene located on chromosome 14q23.2, normally classified as an autosomal recessive retinal disorder, comprising 10% frequency of LCA. Previously defined as a juvenile form of RP, LCA is a severe congenital or early infant-onset form of non-syndromic retinal disease characterised by severe retinal dystrophy, vision loss, nystagmus, an absence of a normal pupil response and an almost non-recordable ERG. LCA was originally identified on the early infant-onset form of non-syndromic inherited visual loss. However, following the original description of the infantile disorder, a subsequent milder form of the same disease presented in the 6th and 7th years of life leading to blindness by the age of 30 and is considered to be on the same spectrum as LCA. This later-onset disease has been referenced by several different names including juvenile and early-onset retinitis pigmentosa, childhood-onset severe retinal dystrophy, Early Onset Severe Retinal Dystrophy (EOSRD) and Severe Early Childhood Onset Retinal Dystrophy (SECORD). Regardless, since the clinical diagnosis does not have a well agreed-upon definition, a more recent structure for nomenclature aiming to define the basis as being on genotype rather than phenotype, is preferable. As of recent reporting, there are an estimated 25 genes causative for LCA. Most of the 25 genes translate proteins for a broad range of functions including phototransduction, the visual cycle and photoreceptor cell development and maintenance, photoreceptor morphogenesis, retinal differentiation, ciliary transport process, phototransduction and retinoid cycle, including the genes for LRAT, RDH12 and RPE65.
Among the most recent study, eight family members were confirmed as affected by genotyping heterozygous for RDH12 c.763delG showing visual acuity ranging from −0.1 to 0.2 logMAR, including constricted visual fields. Clinical characteristics showed a parafoveal and peripapillary ring of hyper-autofluorescence, including mild retinal thinning identified on OCT imaging with reduction in both foveal total retinal and outer nuclear layer thickness. In addition, full-field ERG demonstrated “a rod-cone pattern of dysfunction and large-field pattern electroretinography identified peripheral macular dysfunction”. The four-generation family with adRP, confirmed by whole-genome sequencing, identified a deletion of 1-bp in exon 6 of the RDH12 gene (c.763delG). Finally, according to the researchers, the interpretation of the results showed that, “this variant is predicted to introduce a frameshift leading to a termination codon, 23 codons downstream of the variant”, and all family members reported nyctalopia with demonstrated classical features of a rod-cone dystrophy”.