Clinical and whole-exome sequencing findings in Individuals from Yunnan Province with Familial Exudative Vitreoretinopathy

Background : Familial exudative vitreoretinopathy (FEVR) is a rare inherited retinal disorder characterized by the failure of peripheral retinal vascularization at birth. FEVR can cause further pathological changes, such as neovascularization, exudation, haemorrhage, and retinal detachment, in turn. The molecular diagnosis enables a deeper understanding of this disease, so the differentiation of FEVR is important for the accuracy of genetic counselling. However, to date, only six genes have been identified as being responsible for this disease. Methods : Without a known FEVR gene mutation, six families were enrolled in our study between 2016 and 2017 from the clinical practices of ophthalmologists. The referring physician made a diagnosis for FEVR probands, and clinical data and DNA were collected from each participant. Whole-exome sequencing was used to detect the mutations present in the probands. The raw reads were obtained from Illumina Miseq. Then, an in-house bioinformatics pipeline was performed to detect both single nucleotide variants (SNVs) and small insertions/deletions (InDels). The pathogenic mutations were identified with stringent criteria and were further confirmed by conventional methods and cosegregation in families. Results : Using this approach, bioinformatic predictions showed that six mutations were found in our study: three mutations in the known genes of ZNF408, LRP5 and KIF11 and three mutations in the newly identified genes NR2E3,KRT3 and FOXL2 .To test the hypothesis that cases of FEVR are caused by NR2E3, KRT3 and FOXL2 , probands who were diagnosed as FEVR by a physician using wide-field fluorescein angiography were found to not have any mutations in any of the six known FEVR genes. Compared with previous reports, mutations in NR2E3, KRT3 and FOXL2 are believed to cause a broader spectrum of ocular disease. The NR2E3,KRT3 and FOXL2 genes likely play a role in retinal vascular development. Conclusions : This report is the first to describe FEVR mutations in Yunnan province children with FEVR. This study would provide information on the genetic forms of the disease and direct counselling by analysing the genetic testing and genotype-phenotype interaction.