title: Distinct Clinical Phenotype of Corneal Dystrophy Predicts the p.(Leu450Trp) Substitution in COL8A2.
abstract: OBJECTIVE
  The p.(Leu450Trp) substitution in Collagen, Type VIII, Alpha 2 (COL8A2) is associated with an early-onset corneal dystrophy. Here we identify distinct anterior corneal and keratorefractive changes associated with this disease and replicate its distinguishing endothelial characteristics in a new family.
  
  
  METHODS
  We reviewed clinical data from a large family associated with the p.(Leu450Trp) COL8A2 mutation. We compared clinical photographs and keratometry over an 11-year period. We sought to replicate these findings, and after a 40-year-old male subject presented similarly, we obtained a peripheral blood sample and sequenced COL8A2.
  
  
  RESULTS
  Of 10 individuals with the p.(Leu450Trp) substitution, clinical records noted corneal edema in 6, of which 4 showed epithelial microcystic edema. Eleven-year progression data reveal a marked increase in subepithelial corneal edema and gradual, profound increase in anterior corneal astigmatism. Sequencing of genomic DNA from the unrelated individual predictably identified a c.1349T>G [p.(Leu450Trp)] heterozygous variation in COL8A2. Confocal microscopy confirmed attenuated endothelium, and histopathology revealed no guttae, consistent with findings from a previously identified family.
  
  
  CONCLUSIONS
  Peripheral, anterior microcystic corneal edema represents a characteristic aspect of the phenotype associated with the p.(Leu450Trp) substitution in COL8A2, in at least 2 of 3 known affected families worldwide. We describe long-term progression and Descemet stripping endothelial keratoplasty for this disease for the first time.
authors.affiliation: Wilmer Ophthalmological Institute, Baltimore, MD.
authors.forename: Allen O
authors.initials: AO
authors.lastname: Eghrari
authors.forename: S Amer
authors.initials: SA
authors.lastname: Riazuddin
authors.forename: John D
authors.initials: JD
authors.lastname: Gottsch
mesh_terms: D000328:Adult; D002648:Child; D024102:Collagen Type VIII / Q000235:genetics*; D003317:Corneal Dystrophies, Hereditary / Q000175:diagnosis / Q000235:genetics* / Q000601:surgery; D015715:Corneal Edema / Q000473:pathology; D057111:Descemet Stripping Endothelial Keratoplasty; D005260:Female; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D000069456:Silent Mutation
chemical_list: C443712:COL8A2 protein, human; D024102:Collagen Type VIII