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Molecular Characterization of FZD4, LRP5, and TSPAN12 in Familial Exudative Vitreoretinopathy.

Abstract：

PURPOSE: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.

journal_name

Invest Ophthalmol Vis Sci

journal_title

Investigative ophthalmology & visual science

authors

Seo SH,Yu YS,Park SW,Kim JH,Kim HK,Cho SI,Park H,Lee SJ,Seong MW,Park SS,Kim JY

doi

10.1167/iovs.14-15680

subject

Has Abstract

pub_date

2015-08-01 00:00:00

pages

5143-51

issue

eissn

0146-0404

issn

1552-5783

pii

2424438

journal_volume

pub_type

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Molecular Characterization of FZD4, LRP5, and TSPAN12 in Familial Exudative Vitreoretinopathy.