A clinical and molecular characterisation of CRB1-associated maculopathy

Kamron N. Khan, Anthony Robson, Omar A. R. Mahroo, Gavin Arno, Chris F. Inglehearn, Monica Armengol, Naushin Waseem, Graham E. Holder, Keren J. Carss, Lucy F. Raymond, Andrew R. Webster, Anthony T. Moore, Martin McKibbin, Maria M. van Genderen, James A. Poulter, Michel Michaelides & UK Inherited Retinal Disease Consortium | European Journal of Human Genetics | 2018 | Vol 26 | 687–694 |

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.

Introduction To date, more than 150 disease-associated variants in CRB1 (OMIM #604210) have been described, associated with a range of inherited retinal disease (IRD) phenotypes including Leber congenital amaurosis (LCA), early as well as adult-onset retinitis pigmentosa (RP)—with and without a Coats-like vasculopathy, and more recently macular dystrophy and foveal schisis [1,2,3,4,5,6,7,8,9,10,11]. Characteristic features of CRB1-associated retinopathy include early onset maculopathy, loss of retinal lamination with increased retinal thickness, nummular intraretinal pigmentation, preservation of the para-arteriolar retinal pigment epithelium, and the presence of macular cysts [12]. Expression of the retinal phenotype, however, is variable, even within families, and a number of either genetic or environmental factors have been postulated [13].