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A clinical and molecular characterisation of CRB1-associated maculopathy.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Khan, Kamron N 
Robson, Anthony 
Mahroo, Omar AR 
Arno, Gavin 
Inglehearn, Chris F 

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.

Description

Keywords

Adolescent, Adult, Alleles, Child, Child, Preschool, Electronic Health Records, Eye Proteins, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Infant, Infant, Newborn, Macular Degeneration, Male, Membrane Proteins, Nerve Tissue Proteins, Retinal Photoreceptor Cell Outer Segment, Young Adult

Journal Title

Eur J Hum Genet

Conference Name

Journal ISSN

1018-4813
1476-5438

Volume Title

26

Publisher

Springer Science and Business Media LLC