Whole-Exome Sequencing Analysis Identified Novel Mutations in the TSPAN12 Gene in Chinese Families with Familial Exudative Vitreoretinopathy.

Background: Familial exudative vitreoretinopathy (FEVR, OMIM 133780), characterized by incomplete retinal vascular development and pathological neovascularization, is a severe inherited retinal disorder. Mutations in 10 genes have been reported to be associated with FEVR, but this still leaves ∼50% of FEVR cases to be genetically explained. Purpose: The purpose of this study was to identify novel FEVR-causing mutations and explore the causative mutations in Chinese FEVR families. Methods: Whole-exome sequencing was performed to analyze the genomic DNA of the probands from 121 Chinese FEVR families. Sanger sequencing was carried out to verify all identified mutations. Luciferase assays were used to test the activity of a mutant protein in the Norrin-ß-catenin signaling pathway. Results: Four novel heterozygous TSPAN12 (Tetraspanin 12) mutations, including two single-base substitution mutations and two small-deletion mutations, were identified in these FEVR families: c.1A>G (p.0), c.614G>A (p.G205D), c.695delT (p.V232Gfs*7), and c.833_842del (p.L278Qfs*25). Conclusion: This study revealed the causative mutations in four Chinese FEVR families and identified four novel FEVR-causing mutations, thus expanding the mutation spectrum of FEVR in the Chinese population.

Correlating Changes in the Macular Microvasculature and Capillary Network to Peripheral Vascular Pathologic Features in Familial Exudative Vitreoretinopathy.

PURPOSE: To evaluate the macular microvasculature in patients with familial exudative vitreoretinopathy (FEVR) using OCT angiography (OCTA) and to assess for peripheral vascular changes using widefield fluorescein angiography (WFA). DESIGN: Multicenter, retrospective, comparative, observational case series. PARTICIPANTS: We identified 411 patients with FEVR, examined between September 2014 and June 2018. Fifty-seven patients with FEVR and 60 healthy controls had OCTA images of sufficient quality for analysis. METHODS: Custom software was used to assess for layer-specific, quantitative changes in vascular density and morphologic features on OCTA by way of vessel density (VD), skeletal density (SD), fractal dimension (FD), vessel diameter index (VDI), and foveal avascular zone (FAZ). Widefield fluorescein angiography images were reviewed for peripheral vascular changes including capillary dropout, late-phase angiographic posterior and peripheral vascular leakage (LAPPEL), vascular dragging, venous-venous shunts, and arteriovenous shunts. MAIN OUTCOME MEASURES: Macular microvascular parameters on OCTA and peripheral angiographic findings on WFA. RESULTS: OCT angiography analysis of 117 patients (187 eyes; 92 FEVR patients and 95 control participants) demonstrated significantly reduced VD, SD, and FD and greater VDI in patients with FEVR compared with controls in the nonsegmented retina, superficial retinal layer (SRL), and deep retinal layer (DRL). The FAZ was larger compared with that in control eyes in the DRL (P < 0.0001), but not the SRL (P = 0.52). Subanalysis by FEVR stage showed the same microvascular changes compared with controls for all parameters. Widefield fluorescein angiography analysis of 95 eyes (53 patients) with FEVR demonstrated capillary nonperfusion in all eyes: 47 eyes (49.5%) showed LAPPEL, 32 eyes (33.7%) showed vascular dragging, 30 eyes (31.6%) had venous-venous shunts, and 33 eyes (34.7%) had arteriovenous shunts. Decreasing macular VD on OCTA correlated with increasing peripheral capillary nonperfusion on WFA. Decreasing fractal dimension on OCTA correlated with increasing LAPPEL severity on WFA. CONCLUSIONS: Patients with FEVR demonstrated abnormalities in the macular microvasculature and capillary network, in addition to the peripheral retina. The macular microvascular parameters on OCTA may serve as biomarkers of changes in the retinal periphery on WFA.