A clinical study of patients with novel CDHR1 genotypes associated with late-onset macular dystrophy

Abstract

Purpose To describe the clinical and electrophysiological features of adult-onset macular dystrophy, due to novel combinations of CDHR1 alleles, and compare the associated phenotypes with previous reports. Methods The clinical records of patients with macular dystrophy and biallelic variants in CDHR1 were reviewed. Data analysed included best corrected visual acuity (BCVA), fundus images: autofluorescence (AF) and optical coherence tomography (OCT); full field electroretinography (ERG) and pattern ERG (PERG). Results Seven patients from six pedigrees were ascertained. One patient was homozygous for a known synonymous variant p.(Pro261=), four were compound heterozygous for the p.(Pro261=) variant and a novel allele of CDHR1: p.(Gly188Ser), p.(Met1?), or p.(Val458Asp); one patient was compound heterozygous for two previously unreported variants: c.297+1G>T in trans with p.(Pro735Thr). The range of BCVA at the last clinic review was (6/5-6/60). Autofluorescence showed macular flecks of increased AF in mild cases and patches of reduced AF in severe cases. The OCT showed attenuation of the ellipsoid zone (EZ) in mild cases and loss of the EZ and the outer nuclear layer in severe cases; one patient had subfoveal hyporeflective region between the EZ and the retinal pigment epithelium. The full field ERG was normal or borderline subnormal in all cases, and the PERG was subnormal in mild cases or undetectable in severe cases. Conclusions This report corroborates previous observations that genotypes distinct from those causing pan-retinal dystrophy can cause a milder phenotype, predominantly affecting the macula, and expands the spectrum of these genotypes. The findings in this cohort suggest a potential macular susceptibility to mild perturbations of the photoreceptor cadherin.

Retinal cadherins and the retinal cadherinopathies: Current concepts and future directions

“…This was identified in individuals homozygous for the c.783G>A variant, common in European populations (mean allele frequency of 0.49%) who presented with reduced visual acuity, difficulty in reading, glare, poor contrast and metamorphopsia (Charbel Issa et al, 2019). The symptom complex appeared similar in individuals with different combinations of CDHR1 alleles (Ba-Abbad et al, 2020). Typically, this group does not report nyctalopia (Charbel Issa et al, 2019) although this may be the case if a hypomorphic variant exists in trans with a more severe variant.…”

“…Visual acuity in this group is typically well preserved in at least one eye until later life, in contrast to individuals with biallelic null variants in CDHR1. Moreover, relative preservation of foveal cones may result in retention of a central island of retinal tissue which, when lost, results in a rapid decline in visual acuity (Ba-Abbad et al, 2020, Charbel Issa et al, 2019.…”

An Exploratory Study Provides Insights into MMP9 and Aβ Levels in the Vitreous and Blood across Different Ages and in a Subset of AMD Patients

“…Cadherin-1 was shown to interact with MMP9. A variant of CDHR1, another member of the cadherin superfamily that is specific to photoreceptors, was reportedly associated with inherited retinal dystrophies [ 54 , 55 ] and is a possible target for further scrutiny. Other interacting partners of MMP9 included fellow members of the MMP family such as MMP1, -2, -3 and -14, where links with retinopathies have already been discussed.…”

CDHR1-related late-onset macular dystrophy: further insights

“…We read with interest the series of patients described by Ba-Abbad and colleagues. 1 Whilst biallelic truncating CDHR1 variants result in cone-rod or rod-cone dystrophiesconsistent with the Cdhr1 -/knockout mouse 2 -it is intriguing that certain biallelic splice or missense variants in CDHR1 may result in late-onset macular dystrophy.…”

“…c.783G>ACDHR1 appears to be the most common CDHR1 variant associated with late-onset macular dystrophy, based on mean allele frequency. 1,5 Indeed, when hypomorphic 45 variants are included, CDHR1 was amongst the more common causes of macular and cone-or cone-rod dystrophy in one large series. 6 Although isolated macular dystrophy appears to be the most common phenotype in c.783G>ACDHR1 homozygotes, 5 peripheral retinal degeneration has been reported, 7 suggesting the influence of unknown modifiers which may result in rod photoreceptor degeneration instead of only macular 50 3 involvement.…”