title: Analysis ofCYP1B1in pediatric and adult glaucoma and other ocular phenotypes.
abstract: TheCYP1B1gene encodes an enzyme that is a member of the cytochrome P450 superfamily. Mutations inCYP1B1have been mainly reported in recessive pediatric ocular phenotypes, such as primary congenital glaucoma (PCG) and congenital glaucoma with anterior segment dysgenesis (CG with ASD), with some likely pathogenic variants also identified in families affected with adult-onset primary open angle glaucoma (POAG).
  
  
  
  We examinedCYP1B1in 158 pediatric patients affected with PCG (eight), CG with ASD (22), CG with other developmental ocular disorders (11), juvenile glaucoma with or without additional ocular anomalies (26), and ASD or other developmental ocular conditions without glaucoma (91); in addition, a large cohort of adult patients with POAG (193) and POAG-negative controls (288) was examined.
  
  
  
  Recessive pathogenic variants inCYP1B1were identified in two PCG pedigrees, three cases with CG and ASD, and two families with CG and other ocular defects, such as sclerocornea in one patient and microphthalmia in another individual; neither sclerocornea nor microphthalmia has been previously associated withCYP1B1. Most of the identified causative mutations are new occurrences of previously reported pathogenic alleles with two novel variants identified: a c.1325delC, p.(Pro442Glnfs*15) frameshift allele in a family with PCG and a c.157G>A, p.(Gly53Ser) variant identified in a proband with CG, Peters anomaly, and microphthalmia. Analysis of the family history in theCYP1B1-positive families revealed POAG in confirmed or presumed heterozygous relatives in one family with PCG and two families with ASD/CG; POAG was associated with the c.1064_1076del, p.(Arg355Hisfs*69) allele in two of these pedigrees. Screening of an unrelated POAG cohort identified the same c.1064_1076del heterozygous allele in one individual with sporadic POAG but not in age- and ethnicity-matched POAG-negative individuals. Overall, there was no significant enrichment for mutant alleles inCYP1B1within the POAG cases compared to the controls.
  
  
  
  In summary, these data expand the mutational and phenotypic spectra ofCYP1B1to include two novel alleles and additional developmental ocular phenotypes. The contribution ofCYP1B1to POAG is less clear, but loss-of-function variants inCYP1B1, especially c.1064_1076del, p.(Arg355Hisfs*69), may be associated with an increased risk for POAG.
authors: Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI.
authors: Linda M
authors: LM
authors: Reis
authors: Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI.
authors: Rebecca C
authors: RC
authors: Tyler
authors: Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI.
authors: Eric
authors: E
authors: Weh
authors: Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI.
authors: Kathryn E
authors: KE
authors: Hendee
authors: Kariminejad-Najmabadi Pathology and Genetics Center, Tehran, Iran.
authors: Ariana
authors: A
authors: Kariminejad
authors: Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS.
authors: Omar
authors: O
authors: Abdul-Rahman
authors: Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation and Weill Cornell Medical College, Doha-Qatar.
authors: Tawfeg
authors: T
authors: Ben-Omran
authors: Division of Medical Genetics, Department of Pathology and Department of Pediatrics, Stanford University School of Medicine, Stanford, CA.
authors: Melanie A
authors: MA
authors: Manning
authors: Diskapi Yildirim Beyazit Training and Education Hospital, Genetic Diagnosis Center, Ankara, Turkey
authors: Ahmet
authors: A
authors: Yesilyurt
authors: Marshfield Clinic Research Foundation, Center for Human Genetics Department, Marshfield WI.
authors: Catherine A
authors: CA
authors: McCarty
authors: Marshfield Clinic Research Foundation, Center for Human Genetics Department, Marshfield WI.
authors: Terrie E
authors: TE
authors: Kitchner
authors: Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI.
authors: Deborah
authors: D
authors: Costakos
authors: Department of Pediatrics and Children's Research Institute at the Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI; Department of Ophthalmology, Medical College of Wisconsin, Milwaukee, WI.
authors: Elena V
authors: EV
authors: Semina
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000869:Anterior Eye Segment / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006801:Humans; D006871:Hydrophthalmos / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction
chemical_list: C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1