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Fabiana Louise Motta, Mariana V Salles, Karita Antunes Costa, Rafael Filippelli da Silva, Renan Paulo Martin, Juliana M F Sallum; The Phenotype-Genotype Correlation in Brazilian CRB1 Patients. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2766.
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© ARVO (1962-2015); The Authors (2016-present)
Mutations in at least 250 genes have been associated with inherited retinal dystrophy (IRD). Pathogenic variants in CRB1 lead to a variety of phenotypes ranging from retinitis pigmentosa (RP) to more severe diseases such as Leber congenital amaurosis (LCA). This retrospective study aimed to assess the genotype-phenotype correlation in Brazilian patients with CRB1 variants.
We reviewed 230 medical records of Brazilian patients with molecular tests for IRD. Patients with CRB1 variants were selected and their genetic data, medical history and eye exams were collected. The clinical diagnosis was made based on their signs and symptoms, age of onset and fundus features. The HGMD, ExAC and 1000 Genomes Project databases and Poly-Phen2, SIFT and PROVEAN pathogenicity prediction softwares were used to evaluate variants.
Among the 230 medical records of IRD patients analyzed, 13 cases of unrelated patients with CRB1 variants were selected. Seven patients had clinical diagnoses of LCA, three patients had RP, two patients had cone-rod dystrophy and one patient had early-onset retinal dystrophy. Six new CRB1 variants were identified: four missense variants (p.Leu479Pro, p.Ala921Pro, p.Cys948Arg and p.Asp1031Asn) and two frameshift deletions (c.2536_2542del7 and c.3460_3461delTG). According to the criteria of effect in the protein structure, amino acid conservation, frequency in the population and classification by pathogenic predictors, all variants found can be classified as likely pathogenic. All LCA subjects had more severe pathogenic variants (premature termination or protein tertiary structure changes) in both allele. On the other hand, RP and cone-rod dystrophy patients have mostly missense variants that do not affect cysteines involved in disulfide bonds. Finally, the early-onset retinal dystrophy patient had an intermediate phenotype and genotype, i.e. a missense variant (p.Arg764His) and a premature truncation (p.Arg1390*), but the latter disrupts the protein in the intracellular region, conserving the intracellular FERM motif.
Our data suggest that there was a direct relation between phenotype severity and the mutation effect on protein functionality in the aforementioned CRB1 patients. In summary, the mutation spectrum is proportional to the severity of IRD. In addition, the causal association between CRB1 pathogenic variants and cone-rod dystrophy was reinforced by this study.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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