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.

Retinogenesis of the Human Fetal Retina: An Apical Polarity Perspective

“…One of the main working hypothesis that we draw from our four CRB1-LCA-like models is that CRB2 protein levels may be lower or that a less functional variant is of CRB2 is expressed in CRB1 LCA patients compared to less severe CRB1 retinal diseases [132,298,299]. Clinical reports of CRB1 LCA patients have shown that degeneration can affect all quadrants of the retina while other reports show restriction to the inferior retina [285,288,300,301]. This is highly suggestive of the presence of a modifying factor.…”

Spontaneous Posterior Segment Vascular Disease Phenotype of a Mouse Model,rnv3, Is Dependent on theCrb1rd8Allele

“…These disease characteristics resemble pathologies observed in human macular telangiectasia type 2 (MacTel 2). 30 Over 150 CRB1 alleles 31 have also been reported to cause a multitude of human retinal diseases. CRB1 variants are associated with retinal degenerative phenotypes ranging from Leber congenital amaurosis 8 (MIM# 613835), characterized by congenital or early-onset blindness, to retinitis pigmentosa (RP12, MIM# 600105), a more slowly progressive disease.…”

“…Although null mutations appear to be overrepresented in LCA patients carrying CRB1 mutations, 32 attempts to correlate the CRB1 genotype with unique disease features have not been successful; perhaps the range of disease phenotypes observed is a consequence of interactions with additional genetic and/or environmental factors. 31 , 32 …”

Electroretinogram abnormalities in nonanterior childhood uveitis

“…All eyes with CME had abnormal cone ERGs. Although cones are densely packed in the macula (Osterberg 1935;Jonas et al 1992), macular dysfunction alone contributes only minimally to the full-field cone (Dawson & Maida 1984;Khan et al 2018;Robson et al 2018). The abnormal ERG in the children with CME therefore indicates a global retinal dysfunction and not only macular dysfunction .…”