title: Molecular Characterization of FZD4, LRP5, and TSPAN12 in Familial Exudative Vitreoretinopathy.
abstract: OBJECTIVE
  Familial exudative vitreoretinopathy (FEVR) is a rare hereditary disorder characterized by the failure of peripheral retinal vascularization. The genes FZD4, LRP5, and TSPAN12 are known to be associated with the autosomal inheritance form of FEVR. In this study, we performed mutation screening for FZD4, LRP5, and TSPAN12 in patients with clinical diagnosis of FEVR. In patients with no mutation detected, sequencing analyses for ZNF408, a novel gene potentially related to FEVR, and two other genes related to retinal development, LGR4 and ATOH7, were performed.
  
  
  METHODS
  Mutational studies were done in 51 unrelated patients with diagnosis of FEVR during 2008 to 2012 at the Seoul National University Hospital. These patients were screened previously for NDP gene and confirmed to be negative for mutations. Diagnosis of FEVR was established by ophthalmic examinations. Data collected from medical records included sex, age at diagnosis, clinical presentation, and angiographic findings.
  
  
  RESULTS
  In this study, we identified 3 known mutations, 10 novel variants with high possibility of pathogenicity, and a whole gene deletion in a total of 18 unrelated patients of 51, resulting in 35.3% of patients being genetically confirmed as having FEVR. Among the patients with pathogenic mutations detected, FZD4 mutations accounted for the largest proportion of autosomal inheritance FEVR cases (13/18 patients, 72.2%), followed by LRP5 (4/18 patients, 22.2%) and TSPAN12 (1/18 patients, 5.6%). No pathogenic mutations were identified in ZNF408, LGR4, and ATOH7. A significant difference in FEVR stage and visual acuity was observed according to the gene involved, showing that patients with FZD4 mutations had milder phenotype.
  
  
  CONCLUSIONS
  Mutations of FZD4 accounted for the largest proportion, which could be directly applied to the testing strategy to start with screening for FZD4 mutations. Panel sequencing consisting of related genes would be an alternative choice for the diagnosis of FEVR. Also, genotype-phenotype correlation suggested in this study could be helpful in genetic counseling of the probands and their family members as well.
authors.affiliation: Department of Laboratory Medicine Seoul National University Hospital, Seoul, Korea.
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Seo
authors.affiliation: Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Yu
authors.affiliation: Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sung Wook
authors.initials: SW
authors.lastname: Park
authors.affiliation: Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Jeong Hun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine Seoul National University Hospital, Seoul, Korea.
authors.forename: Hyun Kyung
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine Seoul National University Hospital, Seoul, Korea.
authors.forename: Sung Im
authors.initials: SI
authors.lastname: Cho
authors.affiliation: Department of Laboratory Medicine Seoul National University Hospital, Seoul, Korea.
authors.forename: Hyunwoong
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Laboratory Medicine Seoul National University Hospital, Seoul, Korea.
authors.forename: Seung Jun
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine Seoul National University Hospital, Seoul, Korea.
authors.forename: Moon-Woo
authors.initials: MW
authors.lastname: Seong
authors.affiliation: Department of Laboratory Medicine Seoul National University Hospital, Seoul, Korea 4Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
authors.forename: Sung Sup
authors.initials: SS
authors.lastname: Park
authors.affiliation: Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Kim
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D015785:Eye Diseases, Hereditary; D000080345:Familial Exudative Vitreoretinopathies; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics* / Q000378:metabolism; D056726:Genetic Association Studies; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012164:Retinal Diseases / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D059470:Tetraspanins / Q000235:genetics* / Q000378:metabolism
chemical_list: C402930:FZD4 protein, human; D051157:Frizzled Receptors; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C545100:TSPAN12 protein, human; D059470:Tetraspanins; D004247:DNA