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Abstract

Objective/Purpose
This study evaluates genotype-phenotype correlations in CRB1-retinopathies using standardized phenotypic classification and comprehensive analysis of CRB1-A and CRB1-B involvement alongside in-silico protein modelling analysis.

Design
Retrospective multicentre cohort study.

Subjects
A total of 389 patients with biallelic disease-causing CRB1 variants from 50 international cohorts, including 73 patients from Moorfields Eye Hospital.

Methods
Phenotypes were reclassified using standardized diagnostic criteria. Genotype-phenotype correlations were assessed based on CRB1 isoform involvement and protein domain localisation of variants, supported by in-silico structural modelling.

Main Outcome Measures
Associations between CRB1 variant location, isoform involvement, and clinical phenotypes including Leber congenital amaurosis/early onset severe retinal dystrophy (LCA/EOSRD), retinitis pigmentosa (RP), cone-rod dystrophy (CRD), and macular dystrophy (MD).

Results
All patients had variants affecting CRB1-A, with none exclusively affecting CRB1-B. Mutations specific to CRB1-A, sparing CRB1-B were associated with macular dystrophy. Mutations in exons 6, 7, and 9 were associated to LCA/EOSRD and RP phenotypes, while exon 2 variants were linked to MD. Genotype-phenotype correlations included c.1841G>T p.(Gly614Val) linked to LCA/EOSRD and variants exclusively involving exon 11 and 12. Similarly, the variants c.2506C>A p.(Pro836Thr) and c.498_506del p.(Ile167_Gly169del) were linked to MD.

Conclusions
CRB1-A must be affected for disease manifestation; while sparing of CRB1-B leads to milder phenotypes. Novel genotype-phenotype correlations were found using standardized phenotypic classification. Understanding protein structure and isoform involvement is crucial for accurate diagnosis, prognosis, and the development of targeted therapies.

Publication Type:	Article
Additional Information:	This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Publisher Keywords:	CRB1, CRB1-retinopathy, Crumbs homolog 1, Genotype–phenotype, Inherited retinal disease
Subjects:	R Medicine > RE Ophthalmology
Departments:	School of Health & Medical Sciences School of Health & Medical Sciences > Department of Optometry & Visual Science
SWORD Depositor:	Symplectic Administrator

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