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.

Fig. 1. Patient pedigrees, and multiple sequence alignments of the amino acids substituted in patients with missense changes.

a Pedigrees of seven patients from six unrelated families. The genotypes are shown next to the symbols of affected individuals (solid) and the genotyped asymptomatic relatives. WT wild type allele. b–d Multiple sequence alignments showing conservation of the amino acids substituted in individuals with missense changes of CDHR1. b The glycine at position 188 is preserved across multiple mammalian and non-mammalian species. c Conservation of the proline at position 735 across multiple species. d The valine at position 458 is conserved in primates, and large mammals, but is substituted with isoleucine, which has similar properties, in small mammals, chicken, xenopus, and zebrafish (source: https://www.ncbi.nlm.nih.gov/homologene).

Fig. 2. Fundus autofluorescence (FAF) images and macular optical coherence tomography (OCT) scans of all patients.

a and d The genotypes of all the patients shown to the left of the FAF images. The most representative images for each patient are shown. b and e Short wavelength (488 nm), and medium wavelength (532 nm) FAF images showing abnormal signal in the macular centre in all patients. Note the extensive macular and peripapillary atrophy in the sibling 1-b (second row) compared to the milder macular involvement in sibling 1-a (top row). Case 2, nearly a decade younger than case 1-a, showing alternating increased and decreased AF in the macula with an increased AF signal at the foveal region with perifoveal “gutter” of decreased AF. Case 3 showing flecks of increased AF in the macula, interspersed with spots of decreased AF in the perifoveal region. Case 4 with the novel genotype showed loss of the AF signal nasal to the fovea with preservation of the foveal signal. c and f OCT through the macular centre; top: the right scan shows discontinuity of the ellipsoid zone (EZ) with a thin hyporeflective area between the EZ and the retinal pigment epithelial (RPE) band; the left macular scan shows a larger hyporeflective region anterior to the RPE band, note the stalactite-like pattern likely representing elongated outer segments, the EZ appear thicker on either side of this region; note the relatively thickened choroid in this area in both eyes; case 1-b shows marked disruption of the EZ. cases 2 and 3: the foveal contour is displayed with thinning of the outer nuclear layer (ONL) and disruption of the EZ on either side of the fovea, note the reflectivity of the external limiting membrane (ELM) suggesting early loss of the outer segment before complete loss of the photoreceptors; note the hyperreflective “fleck” temporal to the fovea in case 3. Case 4: preservation of the foveal EZ with disruption on the temporal side and complete loss of EZ nasally with attenuation of the outer nuclear layer (ONL), note the interlaminar bridge-like at the nasal edge. Case 5: almost complete loss of the EZ and attenuation of the outer nuclear layer, note the structures resembling outer retinal tubulation. Case 6: right eye (RE) shows complete loss of the ONL and EZ, left eye (LE) showing only a small hyperreflective line temporal to the fovea, corresponding to the strip on FAF where RPE cells are present.

Fig. 3. Plots of amplitudes and peak times of the main components of full field ERGs of six patients with control data, and unilateral mfERGs of three patients.

Plots of the main full-field ERG component amplitudes and peak times in each eye of the six subjects in the CDHR1 cohort (dark black dots) and in healthy controls (grey dots). Linear regression is through the control data and shows the normal variation and age-related changes in ERG amplitudes across more than six decades. Data are shown for the amplitudes a–d and peak times e–h of the DA10 ERG a-wave a, e and b-waves b, f; LA30 Hz ERG c, g and LA3 ERG b-wave d, h. Data are shown for patient 3 at the age of 29 years and additionally when retested at 30 years. Multifocal ERGs are shown for the left eyes of subject 1a i; subject 4 j and subject 5 k. Note that mfERGs are shown in field view i, k or retinal view (j; obtained using a different recording system).