Hypomorphic CDHR1 variants may result in retinitis pigmentosa with relative preservation of cone function

Abstract

Purpose : Biallelic variants in CDHR1 gene are a known cause of cone-rod and macular dystrophy (MD). Retinitis pigmentosa (RP) has been rarely reported in association with CDHR1 variants and such cases have not been characterised in detail. RP implies relative preservation of foveal cones which we hypothesize may occur in association with hypomorphic CDHR1 alleles. We report deep phenotyping of a patient with CDHR1-related RP and discuss relevance of these observations to known pathophysiology of CDHR1-associated retinal degeneration and gene therapy clinical trials.

Methods : A 54-year-old male referred to retinal genetics clinic with nyctalopia that started aged 23. He underwent full clinical examination, Goldmann visual field testing, fundus photography, short-wavelength FAF, OCT imaging, ERG and microperimetry in 2008 and 2022. Scotopic microperimetry (SM) was performed to assess dark-adapted central rod and cone function. Molecular genetic testing used targeted next generation sequencing (109 genes). DNA base editing strategy analysis looked for theoretically targetable single nucleotide variants with CRISPR-Cas9 base-editing.

Results : Genetic testing identified two mutations: 1)a known hypomorphic missense variant(c.562G>A p,Gly188Ser), 2)a novel variant affecting canonical splice acceptor site(c.784-1G>C). The patient’s clinical presentation, multimodal retinal imaging studies, ERG and mesopic microperimetry (MM) were consistent with progressive rod-cone dystrophy (i.e. classic RP). MM, (considered a cone driven test), showed overall impaired sensitivity compared with normal limits. There were no scotomas within the central field as seen in cone-rod and macular dystrophy patients. SM suggested some preservation of cone function over rod function although both are severely impaired. CRISPR analysis found adenosine base editor could be suitable for correcting the missense variant c.562G>A p (Gly188Ser).

Conclusions : Deep phenotyping of CDHR1-associated RP shows a relative preservation of cone function in the presence of a hypomorphic allele and may be considered a hypomorphic disease phenotype. The demonstration of progressive loss of rod and cone function suggests that this group may benefit from gene therapy. Further work is required to identify the modifying factors determining disease phenotype, since MD– which spares rods may also result from the presence of hypomorphic CDHR1 alleles.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.