CDHR1-associated retinal degeneration: clinical phenotypes, natural history and molecular genetics from 135 cases

Abstract

Purpose : To systematically describe the clinical phenotypes, natural history, molecular genetics, genotype-phenotype associations and estimated genetic prevalence of CDHR1-associated retinal degeneration.

Methods : An international, multi-centre, retrospective cohort study that included 135 individuals (65 males) with retinal degeneration attributed to biallelic CDHR1 variants. Data relating to clinical history, symptoms and age of onset, best-corrected visual acuity, multimodal retinal imaging including fundus photography, SD-OCT and fundus autofluorescence (Heidelberg Spectralis), electroretinography, visual fields and molecular genetic testing were extracted from medical records. Retinal thickness was measured on SD-OCT. Protein modelling was used to determine the effects of missense variants. Genetic prevalence was estimated by disease phenotype using the Hardy-Weinberg equilibrium and allele frequencies of disease-associated mutations.

Results : 100 individuals with cone-rod dystrophy (CRD) harboured biallelic truncating or predicted severe missense variants with symptom onset at a median age of 20 years. 32 individuals had macular degeneration (MD) with at least one hypomorphic allele (typically the common c.783G>A variant) and symptom onset at a median of 44 years. Multimodal retinal imaging characteristics of CRD and MD patients are presented in Figure 1. Severe visual impairment occurred earlier in CRD (median 41 years) versus MD (median 71 years) (n=126; P<0.0001; 95% CI presented in Figure 2). Retinal thickness was reduced in the central 3mm and 6mm versus controls (n=93; P<0.0001) in both CRD and MD groups. 115 disease-associated CDHR1 variants were identified, of which 25 were novel. Genetic prevalence estimates suggest >200,000 affected individuals worldwide, 95% of whom are expected to develop MD.

Conclusions : The natural history of CDHR1-associated retinal degeneration is of slow progression with a clear therapeutic window for intervention. The main disease phenotypes of CRD and MD can be generally predicted based on the underlying pathogenic genetic variants. Misclassification of CDHR1-associated MD as age-related macular degeneration with underdiagnosis is likely based on genetic prevalence estimates.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Figure 1. Retinal imaging characteristics in CDHR1-associated retinal degeneration.

 

Figure 2. Natural history of visual decline in CDHR1-associated retinal degeneration.