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

Purpose: Searched for novel bi-allelic CRB1 mutations, then analyzed
the CRB1 literature at the genotypic and phenotypic levels from
439 patients worldwide. Approach: We screened various variables such as
the CRB1 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.
Results: We first identified a novel bi-allelic missense in the exon 9 of
CRB1; c.2936G>A; p.(Gly979Asp) associated with RCD. CRB1
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<0.05). Of the 154 articles retrieved from PubMed, 96 studies
with 439 bi-allelic CRB1 patients were included. 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<0.05). In contrast, homozygous nonsense
mutations were associated with macular pigments, periphery pigments, and a
high risk of LCA (P<0.05) and increased BCVA OU (best-corrected
visual acuity) levels. 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<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. 
Conclusion: This meta-analysis updated the literature and identified
genotype-phenotype associations in bi-allelic CRB1 patients.