Novel Genotype-Phenotype Correlations in CRB1-Retinopathies: Insights from Isoforms and Protein Domains Linked to...

This study evaluates genotype-phenotype correlations in CRB1-retinopathies using standardized phenotypic classification and comprehensive analysis of Crumbs homolog 1 (CRB1)-A and CRB1-B involvement alongside in silico protein modeling analysis.

Retrospective multicenter cohort study.

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

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

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, and macular dystrophy (MD).

All patients had variants affecting CRB1-A, with none exclusively affecting CRB1-B. Mutations specific to CRB1-A, sparing CRB1-B were associated with MD. Mutations in exons 6, 7, and 9 were associated to LCA/EOSRD and RP phenotypes, whereas 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.

Crumbs homolog 1-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.

The authors have no proprietary or commercial interest in any materials discussed in this article.