Genotype-Phenotype Correlations in CYP1B1-Associated Primary Congenital Glaucoma Patients Representing Two Large Cohorts from India and Brazil

Abstract

BackgroundPrimary congenital glaucoma (PCG), occurs due to the developmental defects in the trabecular meshwork and anterior chamber angle in children. PCG exhibits genetic heterogeneity and the CYP1B1 gene has been widely implicated worldwide. Despite the diverse mutation spectra, the clinical implications of these mutations are yet unclear. The present study attempted to delineate the clinical profile of PCG in the background of CYP1B1 mutations from a large cohort of 901 subjects from India (n=601) and Brazil (n=300).MethodsGenotype-phenotype correlations was undertaken on clinically well characterized PCG cases from India (n=301) and Brazil (n=150) to assess the contributions of CYP1B1 mutation on a set of demographic and clinical parameters. The demographic (gender, and history of consanguinity) and quantitative clinical (presenting intraocular pressure [IOP] and corneal diameter [CD]) parameters were considered as binary and continuous variables, respectively, for PCG patients in the background of the overall mutation spectra and also with respect to the prevalent mutations in India (R368H) and Brazil (4340delG). All these variables were fitted in a multivariate logistic regression model using the Akaike Information Criterion (AIC) to estimate the adjusted odds ratio (OR) using the R software (version 2.14.1).ResultsThe overall mutation spectrum were similar across the Indian and Brazilian PCG cases, despite significantly higher number of homozygous mutations in the former (p=0.024) and compound heterozygous mutations in the later (p=0.012). A wide allelic heterogeneity was observed and only 6 mutations were infrequently shared between these two populations. The adjusted ORs for the binary (demographic) and continuous (clinical) variables did not indicate any susceptibility to the observed mutations (p>0.05).ConclusionsThe present study demonstrated a lack of genotype-phenotype correlation of the demographic and clinical traits to CYP1B1 mutations in PCG at presentation. However, the susceptibility of these mutations to the long-term progression of these traits are yet to be deciphered.

CYP1B1 Gene and Phenotypic Correlation in Patients From Northeastern Brazil With Primary Congenital Glaucoma

“…The present study did not find significant differences in the phenotype among the PCG population, with and without CYP1B1 variants, although the limited costs of the research and consequently the limited number of participants may have contributed to this conclusion. Other studies have reported similar results 6,29…”

“…In contrast, there is a discrepancy between these numbers and those obtained in populations with high consanguinity rates such as in Morocco (40%), Iran (70%), Kuwait (70.6%), and Saudi Arabia 6,26–28. Different results were found in previous Brazilian studies such as those performed by De Melo et al29 and Della Paolera et al30 with 44% and 30%, respectively. Nevertheless, these studies did not include patients from northeastern Brazil in their samples, which is the object of the present study.…”

Analysis of CYP1B1 gene mutations in primary congenital glaucoma patients

“…The alteration occurrences of CYP1B1 in PCG were almost similar in India and Brazil; For India; it showed a slightly higher proportion of homozygous alterations; contrary to Brazil; where the heterozygous alterations was higher. 22 Six mutations shared between these two patients (S476P, R368H, A443G, P437L, 8214_8215delAG and 8037_8046dup10). The most frequent mutation is found in India which is R368H and that has also been found in Korea and Morocco.…”

Exome Sequencing in a Swiss Childhood Glaucoma Cohort Reveals CYP1B1 and FOXC1 Variants as Most Frequent Causes

“…Several studies have attempted to compare the clinical phenotype and genotype in PCG patients with and without pathogenic variants in CYP1B1; however, results to date are inconclusive. 17,24,25 More promising is the approach taken by Hollander et al 26 and García-Antón et al, 22 namely assessing the histologic angle tissue and enzyme activity. Their results suggest that CYP1B1 null alleles lead to an underdeveloped post-trabecular outflow pathway, making these patients more suitable candidates for fistulating rather than nonfistulating surgery.…”