A clinical and molecular characterisation of CRB1-associated maculopathy

Abstract

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.

Fig. 1

Optical coherence tomography and fundus autofluorescence imaging of patients with CRB1-associated maculopathy. a Optical coherence tomography (OCT) line scans with near infra-red reflectance images showing scan position (inset). Macro and microcystic oedema is evident in patients MEH1, 2 and BDC6. Foveolar preservation of the ellipsoid zone is present in MEH1, MEH2, Leeds 1 and BDC6. More significant degeneration has already occurred in MEH3 and 4, including loss of the external limiting membrane and outer nuclear layers. Varying degree and extent of macular thickening and loss of lamination is evident in MEH3, 4 and 5. b Fundus autofluorescence images from the same time point as OCT scans. Macular autofluorescence is abnormal in all cases, but again with a degree of foveolar sparing. In the oldest patients, the zone of abnormal autofluorecence extends to include the peripapillary retina—initially an increase in signal (Leeds 1), which is likely to evolve to reduced (MEH4) and then lost autofluorescence (MEH3 and 5)