title: Identification of Novel Variants in LTBP2 and PXDN Using Whole-Exome Sequencing in Developmental and Congenital Glaucoma.
abstract: BACKGROUND
  Primary congenital glaucoma (PCG) is the most common form of glaucoma in children. PCG occurs due to the developmental defects in the trabecular meshwork and anterior chamber of the eye. The purpose of this study is to identify the causative genetic variants in three families with developmental and primary congenital glaucoma (PCG) with a recessive inheritance pattern.
  
  
  METHODS
  DNA samples were obtained from consanguineous families of Pakistani ancestry. The CYP1B1 gene was sequenced in the affected probands by conventional Sanger DNA sequencing. Whole exome sequencing (WES) was performed in DNA samples of four individuals belonging to three different CYP1B1-negative families. Variants identified by WES were validated by Sanger sequencing.
  
  
  RESULTS
  WES identified potentially causative novel mutations in the latent transforming growth factor beta binding protein 2 (LTBP2) gene in two PCG families. In the first family a novel missense mutation (c.4934G>A; p.Arg1645Glu) co-segregates with the disease phenotype, and in the second family a novel frameshift mutation (c.4031_4032insA; p.Asp1345Glyfs*6) was identified. In a third family with developmental glaucoma a novel mutation (c.3496G>A; p.Gly1166Arg) was identified in the PXDN gene, which segregates with the disease.
  
  
  CONCLUSIONS
  We identified three novel mutations in glaucoma families using WES; two in the LTBP2 gene and one in the PXDN gene. The results will not only enhance our current understanding of the genetic basis of glaucoma, but may also contribute to a better understanding of the diverse phenotypic consequences caused by mutations in these genes.
authors.affiliation: Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Shazia
authors.initials: S
authors.lastname: Micheal
authors.affiliation: Department of Pediatric Ophthalmology, Al-Shifa Eye Trust Hospital Jhelum Road, Rawalpindi, Pakistan.
authors.forename: Sorath Noorani
authors.initials: SN
authors.lastname: Siddiqui
authors.affiliation: Department of Pediatric Ophthalmology, Al-Shifa Eye Trust Hospital Jhelum Road, Rawalpindi, Pakistan.
authors.forename: Saemah Nuzhat
authors.initials: SN
authors.lastname: Zafar
authors.affiliation: School of Biosciences, University of Westminster, London, United Kingdom.
authors.forename: Aftab
authors.initials: A
authors.lastname: Iqbal
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Muhammad Imran
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Department of Ophthalmology, Radboud University Medical Centre, Nijmegen, the Netherlands.|Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003315:Cornea / Q000473:pathology*; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics*; D004247:DNA / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D005901:Glaucoma / Q000151:congenital* / Q000235:genetics*; D006801:Humans; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D010154:Pakistan; D010544:Peroxidases; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000097423:Peroxidasin
chemical_list: D000951:Antigens, Neoplasm; D065633:Cytochrome P-450 CYP1B1; D004247:DNA; D053779:Latent TGF-beta Binding Proteins; D010544:Peroxidases; D017472:Receptors, Interleukin-1; C509035:LTBP2 protein, human; C535215:PXDN protein, human; D000097423:Peroxidasin; C585496:CYP1B1 protein, human