Genotype-phenotype associations in CRB1 bi-allelic patients: a novel mutation and a systematic review

<p><span><strong>Purpose</strong>: Searched for novel bi-allelic <em>CRB1</em> mutations, then analyzed the <em>CRB1</em> literature at the genotypic and phenotypic levels from 439 patients worldwide.</span></p> <p><span><strong>Approach</strong>: We screened various variables such as the <em>CRB1</em> mutation types, domains, exons, and genotypes and their relation with specific ocular phenotypes. An emphasis was given for the bi-allelic missense and nonsense mutations because of their high prevalence compared to other mutation types. Finally, we quantified the effect of various non-modifiable factors over the BCVA OU using multivariate linear regression models and identified genetic interactions.</span></p> <p><span><strong>Results</strong>: We first identified a novel bi-allelic missense in the exon 9 of <em>CRB1</em>; c.2936G&gt;A; p.(Gly979Asp) associated with RCD. <em>CRB1</em> mutation type, exons, domains, and genotype distribution vary significantly according to Fundus characteristics, such as peripheral pigmentation and condition, optic disc, vessels, macular, and pigmentation (P&lt;0.05). Of the 154 articles retrieved from PubMed, 96 studies with 439 bi-allelic <em>CRB1</em> patients were included. </span><span>Missense mutations were significantly associated with an absence of macular pigments, pale optic disc, and periphery pigmentation, resulting in a higher risk of RCD (P&lt;0.05). In contrast, homozygous nonsense mutations were associated with macular pigments, periphery pigments, and a high risk of LCA (P&lt;0.05) and increased BCVA OU (best-corrected visual acuity) levels.</span><span> We found that age, mutation types, and inherited retinal diseases were critical determinants of BCVA OU as they significantly increased it by 33%, 26%, and 38%, respectively (P&lt;0.05). Loss of function alleles additively increased the risk of LCA, with nonsense having a more profound effect than indels. Finally, our analysis showed that p.(Cys948Tyr) and p.(Lys801Ter) and p.(Lys801Ter); p.(Cys896Ter) might interact to modify BCVA OU levels. </span></p> <p><span><strong>Conclusion</strong>: This meta-analysis updated the literature and identified genotype-phenotype associations in bi-allelic <em>CRB1</em> patients.</span></p>