title: Genotype-Phenotype Correlations in CYP1B1-Associated Primary Congenital Glaucoma Patients Representing Two Large Cohorts from India and Brazil.
abstract: BACKGROUND
  Primary 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).
  
  
  METHODS
  Genotype-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).
  
  
  RESULTS
  The 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).
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Center of Molecular Biology and Genetic Engineering, University of Campinas, Campinas, SP, Brazil.
authors.forename: Mônica Barbosa
authors.initials: MB
authors.lastname: de Melo
authors.affiliation: Jasti V Ramanamma Childrens Eye Care Centre, L.V. Prasad Eye Institute, Hyderabad, India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mandal
authors.affiliation: Department of Ophthalmology, Federal University of São Paulo, SP, Brazil.
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Tavares
authors.affiliation: Centre for Clinical Epidemiology and Biostatistics, L.V. Prasad Eye Institute, Hyderabad, India.
authors.forename: Mohammed Hasnat
authors.initials: MH
authors.lastname: Ali
authors.affiliation: Kallam Anji Reddy Molecular Genetics Laboratory, L.V. Prasad Eye Institute, Hyderabad, India.
authors.forename: Meha
authors.initials: M
authors.lastname: Kabra
authors.affiliation: Department of Ophthalmology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
authors.forename: José Paulo Cabral
authors.initials: JP
authors.lastname: de Vasconcellos
authors.affiliation: Jasti V Ramanamma Childrens Eye Care Centre, L.V. Prasad Eye Institute, Hyderabad, India.
authors.forename: Sirisha
authors.initials: S
authors.lastname: Senthil
authors.affiliation: Department of Ophthalmology, Federal University of São Paulo, SP, Brazil.
authors.forename: Juliana M F
authors.initials: JM
authors.lastname: Sallum
authors.affiliation: Kallam Anji Reddy Molecular Genetics Laboratory, L.V. Prasad Eye Institute, Hyderabad, India.
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Kaur
authors.affiliation: Department of Ophthalmology, University of São Paulo School of Medicine, São Paulo, SP, Brazil.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Betinjane
authors.affiliation: Department of Ophthalmology, Federal University of São Paulo, SP, Brazil.
authors.forename: Christiane R
authors.initials: CR
authors.lastname: Moura
authors.affiliation: Department of Ophthalmology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Jayter S
authors.initials: JS
authors.lastname: Paula
authors.affiliation: Department of Ophthalmology, Federal University of São Paulo, SP, Brazil.
authors.forename: Karita A
authors.initials: KA
authors.lastname: Costa
authors.affiliation: Molecular Ophthalmic Genetics Laboratory, Surgical Research Center, Department of Surgery, University of Connecticut Health Center, Farmington, Connecticut, United States of America.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Sarfarazi
authors.affiliation: Department of Ophthalmology, Irmandade da Santa Casa de Misericordia de São Paulo, School of Medical Sciences, São Paulo, SP, Brazil.
authors.forename: Mauricio Della
authors.initials: MD
authors.lastname: Paolera
authors.affiliation: Department of Ophthalmology, University of São Paulo School of Medicine, São Paulo, SP, Brazil.
authors.forename: Simone
authors.initials: S
authors.lastname: Finzi
authors.affiliation: Genetics Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Victor E F
authors.initials: VE
authors.lastname: Ferraz
authors.affiliation: Department of Ophthalmology, Faculty of Medical Sciences, University of Campinas, Campinas, SP, Brazil.
authors.forename: Vital P
authors.initials: VP
authors.lastname: Costa
authors.affiliation: Department of Ophthalmology, Federal University of São Paulo, SP, Brazil.
authors.forename: Rubens
authors.initials: R
authors.lastname: Belfort
authors.affiliation: Kallam Anji Reddy Molecular Genetics Laboratory, L.V. Prasad Eye Institute, Hyderabad, India.
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Chakrabarti
mesh_terms: D000483:Alleles; D000867:Anterior Chamber / Q000473:pathology; D001938:Brazil; D002675:Child, Preschool; D000013:Congenital Abnormalities / Q000235:genetics*; D003315:Cornea / Q000473:pathology; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies / Q000379:methods; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005901:Glaucoma / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007194:India; D007223:Infant; D007429:Intraocular Pressure / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D014065:Tonometry, Ocular / Q000379:methods; D014129:Trabecular Meshwork / Q000473:pathology
chemical_list: C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1