Submission Details

The RDH5 gene was first reported in relation to autosomal recessive “RDH5-related retinopathy” in 1999 (Yamamoto et al, PMID 10369264). Biallelic variants in RDH5 have been reported in individuals with various clinical features. Many individuals are reported to have fundus albipunctatus, with night blindness from childhood, stationary or slow progression of rod abnormalities, frequent and progressive cone abnormalities in older age, the presence of white dots in the retina, and cone dystrophy developing with age in some patients while others have been diagnosed with retinitis pigmentosa. Due to the variability in phenotype, for this curation, these phenotypes have been lumped together as “RDH5-related retinopathy”. To date, over 40 variants in the RDH5 gene have been reported in individuals with retinal dystrophy, and most of them are missense variants (Skorczyk-Werner et al 2015, PMID 25820994). Here, eleven unique variants in eleven probands were curated from seven publications (Yamamoto et al, 1999, PMID 10369264; Gonzalez-Fernandez et al, 1999, PMID 10617778; Nakamura et al, 2000, PMID 11053295; Wada et al, 2001, PMID 11448328; Pras et al, 2012, PMID 22815624; Almutairi et al, 2020, PMID 33369259; Katagiri et al, 2020, PMID 32232344). These variants included missense, nonsense, and frameshift variants in addition to one variant, c.928delCinsGAAG (p.Leu310GluVal), which is commonly identified in Japanese patients (Nakamura et al, 2000, PMID 11053295; Katagiri et al, 2020, PMID 32232344; Skorczyk-Werner et al 2015, PMID 25820994). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. Of note, in two reported patients, only a single variant was identified (Pras et al, 2012, PMID: 22815624). However, there is currently insufficient evidence to indicate that a single RDH5 variant can cause retinal disease. The gene-disease relationship is also supported by experimental evidence including the function of the RDH5 gene product in the visual cycle, which is consistent with the features noted in patients with biallelic variants (Driessen et al, 1995, PMID 7544779), the expression pattern of RDH5, specifically in the retinal pigment epithelium (Driessen et al, 1995, PMID 7544779; Swamy and McGaughey, 2019, PMID 31343654), physical interaction of RDH5 with RPE65, another gene implicated in retinal dystrophy with a role in the visual cycle (Aoun et al, 2021, PMID 34281261), and the features of an rdh5 knock-out mouse (Driessen et al, 2000, PMID 10825191). In summary, RDH5 is definitively associated with autosomal recessive RDH5-related 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 Retina GCEP (SOP v8) on September 2, 2021.