Submission Details

The *CDHR1 *gene was first reported in relation to autosomal recessive cone-rod dystrophy (PMID 20463681), and retinal degeneration (PMID 20463681) in 2010. CDHR1-related retinopathy can manifest in various but progressive forms of retinal degeneration, including cone-rod dystrophy, rod-cone dystrophy, and late-onset macular degeneration (LOMD) (PMID 30060493). The onset of clinical symptoms of CDHR1-related retinopathy may span a wide range (5-45 years). Clinically, patients exhibit reduced visual acuity, color vision defects, photophobia, nyctalopia, visual field defects (constricted VF or central scotoma), and ERG defects (PMID 23379534). Interestingly, one relatively common synonymous variant, c.783G>A, resulting in skipping of exon 8 and leading to the in-frame deletion of 48 amino acids of the CDHR1 ectodomain, has been frequently reported as a hypomorphic variant causing late-onset macular dystrophy (PMIDs 30060493, 23379534). In a recent study, the c.783G>A variant was also noted to confer incomplete penetrance (PMID 30060493). Five variants (missense, synonymous, and pLOF) that have been reported in five publications (PMIDs 20463681, 23379534, 30060493, 20463681, 23379534) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. There are 99 pathogenic or likely pathogenic CDHR1 variants listed on ClinVar (PMID 23379534). The mechanism of pathogenicity is reported to be loss of function (LOF). This gene-disease relationship is also supported by functional studies in mice, where homozygous Cdhr1 knock-out mice showed progressive outer retinal degeneration (PMID 20463681).

In summary, CDHR1 is definitively associated with autosomal recessive retinopathy. This has been repeatedly demonstrated in research and clinical diagnostic settings and has been upheld over time.