Novel Genotype-Phenotype Correlations in

Objective: This study evaluates genotype-phenotype correlations in Design: Retrospective multicenter cohort study. Subjects: A total of 389 patients with biallelic disease-causing Methods: 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. Main Outcome Measures: Associations between 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 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. Conclusions: 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. Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.