In Search of Novel Disease-Causing Genes of Familial Exudative Vitreoretinopathy (FEVR) - a Genetically Heterogeneous Eye Disease

Abstract

 

Purpose

 

Familial exudative vitreoretinopathy (FEVR) is a rare genetic disease that can cause visual impairment and retinal detachment due to abnormal retinal vascularization. To date, there are four major disease genes associated with FEVR: NDP, FZD4, LRP5, and TSPAN12, accounting for ~50% of FEVR cases. The goal of our study is to identify the molecular basis for the remaining unsolved FEVR cases.

 

Methods

 

Genetic variants in a cohort of about 100 FEVR patients were evaluated using a two-step strategy. First, targeted panel next generation sequencing (NGS) was performed to screen variants in all known FEVR-causing and other retinal disease genes. Patients for whom no probable disease-causing variant was found were subject to whole exome sequencing (WES). Candidate disease-causing variants and genes were identified and further verified using Sanger sequencing. Future functional validation in animal models is planned.

 

Results

 

Known and novel variants in FEVR-associated disease genes accounted for ~40% of our cohort. For the unsolved cases, we found candidate genes enriched in both large families and sporadic cases. These genes have functional implications in tissue vascularization based on mouse phenotypes. Variants in suspected genes also recurred in multiple cases, providing further evidence of disease association.

 

Conclusions

 

A large number of novel alleles in known FEVR genes have been identified in our study. These novel variants provide additional structural and functional information about these disease genes, and their roles in the Wnt signaling pathway. In addition, despite screening for all known retinal disease genes, the molecular cause of significant portion of the FEVR patient remains undetermined. Therefore, it is very likely that many novel FEVR-causing genes are yet to be identified. Indeed, several candidate disease genes have been identified by WES.

 

 

Keywords: 700 retinal neovascularization • 440 candidate gene analysis • 539 genetics