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Familial exudative vitreoretinopathy (FEVR) is a blindness-causing retinal vascular disease characterized by incomplete vascularization of the peripheral retina and by the absence or abnormality of the second/tertiary capillary layers in the deep retina. Variants in known FEVR disease genes can only explain about 50% of FEVR-affected cases. We aim to identify additional disease genes in patients with FEVR. We applied exome sequencing analysis in a cohort of 49 FEVR families without pathogenic variants in known FEVR genes. Functions of the affected proteins were evaluated by reporter assay. Knockout mouse models were generated by endothelial-specific Cre line. Three novel rare heterozygous variants in Notch ligand JAG1 were identified in FEVR families-c.413C>T p. (A138V), c.1415G>A p. (R472H), and c.2884A>G p. (T962A)-and verified by Sanger sequencing analysis. Notch reporter assay revealed that mutant JAG1 proteins JAG1-A138V and JAG1-T962A lost almost all of their activities, and JAG1-R472H lost approximately 50% of its activity. Deletion of Jag1 in mouse endothelial cells resulted in reduced tip cells at the angiogenic front and retarded vessel growth, reproducing FEVR-like phenotypes. Our data suggest that JAG1 is a novel candidate gene for FEVR and pinpoints a potential target for therapeutic intervention.


Lin Zhang, Xiang Zhang, Huijuan Xu, Lulin Huang, Shanshan Zhang, Wenjing Liu, Yeming Yang, Ping Fei, Shujin Li, Mu Yang, Peiquan Zhao, Xianjun Zhu, Zhenglin Yang. Exome sequencing revealed Notch ligand JAG1 as a novel candidate gene for familial exudative vitreoretinopathy. Genetics in medicine : official journal of the American College of Medical Genetics. 2020 Jan;22(1):77-84

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PMID: 31273345

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