Optical Coherence Tomography Angiography in Familial Exudative Vitreoretinopathy: Clinical Features and Phenotype-Genotype Correlation

Chen, Chonglin; Liu, Chengxi; Wang, Zhirong; Sun, Limei; Zhao, Xiujuan; Li, Songshan; Luo, Xiaoling; Zhang, Aiyuan; Chong, Victor; Lü, Lin; Ding, Xiaoyan

doi:10.1167/iovs.18-25377

Cited by 23 publications

(31 citation statements)

References 38 publications

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“…This finding was consistent with the former studies, in which LRP5 was considered one of the main causes of FEVR, especially in patients with mild FEVR. 24 Our study provided new evidence for this genotypephenotype association. Furthermore, we carefully reviewed the published reports and compared the mutation spectrum: in our previous cohort, 52.3% (23/44) was missense variant, 9,19 which is lower than this current one.…”

Section: Discussionsupporting

confidence: 57%

Next-Generation Sequencing in the Familial Exudative Vitreoretinopathy-Associated Rhegmatogenous Retinal Detachment

Chen

Wang

Sun

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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The purpose of this study was to investigate the genetic mutation spectrum in Chinese patients with familial exudative vitreoretinopathy-associated rhegmatogenous retinal detachment (FEVR-RRD) and to analyze the preliminary genotype-phenotype association. METHODS. In this consecutive, cross-sectional study, 54 patients with FEVR-RRD were studied. Comprehensive ophthalmic examinations and targeted next-generation sequencing were performed in all patients. The genotype-phenotype association was also analyzed. RESULTS. Causative mutations were identified in 38.9% (21/54) of patients (14/54 in LRP5, 4/ 54 in FDZ4, and 3/54 in TSPAN12). The study identified 22 potentially pathogenic mutations in 21 unrelated FEVR probands, and 14 were novel (10/15 in LRP5, 1/4 in FZD4, and 3/3 in TSPAN12). Furthermore, to explore the genotype-phenotype association, late-phase angiographic posterior and peripheral leakage (LAPPEL) was identified in 100% (4/4) of patients with FZD4 mutations and 100% (3/3) of patients with TSPAN12 mutations but only in 42.9% (6/14) of patients with LRP5 mutations. Extraretinal neovascularization (ERNV) was found in 100% (4/4) of patients with FZD4 mutations and in 66.7% (2/3) of patients with TSPAN12 mutations, but only in 21.4% (3/14) of patients with LRP5 mutations. CONCLUSIONS. The positive rate for pathogenic mutations in the known FEVR-associated genes was 38.9% (21/54). Among the mutations, LRP5 mutation was the predominant, accounting for 66.7% (14/21) of genetic positive patients. Patients with FEVR-RRD due to LRP5 mutations have less retinal vascular leakage or neovasculization than do patients with FEVR-RRD due to TSPAN12/FZD4 mutations. Moreover, 14 novel variants were found, which provided a deeper understanding of this disease.

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Section: Discussionsupporting

confidence: 57%

Next-Generation Sequencing in the Familial Exudative Vitreoretinopathy-Associated Rhegmatogenous Retinal Detachment

Chen

Wang

Sun

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Small FAZ areas were defined to be all those with an area of <0.18 mm 2 , as defined in previous studies. 23 The quantification of foveal thickness, temporal thinning, and foveal pit width in the structural OCT images were analyzed using the built-in segmentation and analysis software of the Heidelberg Eye Explorer (Version 2.3.3; Heidelberg Engineering). Correct segmentation was verified by an experienced examiner and-when necessary-manually corrected.…”

Section: Image Processing and Data Analysismentioning

confidence: 99%

Phenotypic Spectrum of the Foveal Configuration and Foveal Avascular Zone in Patients With Alport Syndrome

Hess

Pfau

Wintergerst

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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spectrum of the foveal configuration and foveal avascular zone in patients with Alport syndrome. Invest Ophthalmol Vis Sci. 2020;61(2):5. https://doi.org/10.1167/iovs.61.2.5 PURPOSE.To investigate characteristics of the foveal pit and the foveal avascular zone (FAZ) in patients with Alport syndrome (AS), a rare monogenetic disease due to mutations in genes encoding for collagen type IV. METHODS.Twenty-eight eyes of nine patients with AS, and five autosomal-recessive carriers and 15 eyes from 15 age-similar healthy control subjects were examined using optical coherence tomography (OCT) and OCT-angiography (OCT-A). Foveal configuration and FAZ measures including the FAZ area, circularity, and vessel density in the central 1°and 3°were correlated. RESULTS.Foveal hypoplasia was found in 10 eyes from seven patients with either genotype. In contrast, a staircase foveopathy was found in seven eyes of four X-linked AS patients. The average FAZ area did not differ significantly between AS patients and control subjects (mean ± SD 0.24 ± 0.24 mm 2 vs. 0.21 ± 0.09 mm 2 ; P = 0.64). Five eyes showed absence or severe anomalies of the FAZ with crossing macular capillaries that was linked to the degree of foveal hypoplasia on OCT images leading to a significant inverse correlation of FAZ area and foveal thickness (r = −0.88; P < 0.001). In contrary, female patients with X-linked mutations exhibited a significantly greater FAZ area (0.48 ± 0.30 mm 2 vs. 0.21 ± 0.09 mm 2 ; P = 0.007), in line with OCT findings of a staircase foveopathy. CONCLUSIONS.The foveal phenotypic spectrum in AS ranges from foveal hypoplasia and absence of a FAZ to staircase foveopathy with an enlarged FAZ. Because the development of the FAZ and foveal pit are closely related, these findings suggest an important role for collagen type IV in foveal development and maturation.

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“…surface of the retina together with the intraretinal vasculature, comprising two tiers of capillaries that flank the inner nuclear layer (INL), supply the metabolic requirements of the inner two layers of retinal neurons and glia. In FEVR patients (17) and mouse models (18,19), reduced or absent Norrin/Frizzled4 signaling results in reduced or aborted development of the intraretinal and peripheral retinal blood vessels.…”

Section: Significancementioning

confidence: 99%

Hypoxia tolerance in the Norrin-deficient retina and the chronically hypoxic brain studied at single-cell resolution

Heng

Rattner

Stein-O’Brien

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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The mammalian CNS is capable of tolerating chronic hypoxia, but cell type-specific responses to this stress have not been systematically characterized. In the Norrin KO (NdpKO) mouse, a model of familial exudative vitreoretinopathy (FEVR), developmental hypovascularization of the retina produces chronic hypoxia of inner nuclear-layer (INL) neurons and Muller glia. We used single-cell RNA sequencing, untargeted metabolomics, and metabolite labeling from 13C-glucose to compare WT and NdpKO retinas. In NdpKO retinas, we observe gene expression responses consistent with hypoxia in Muller glia and retinal neurons, and we find a metabolic shift that combines reduced flux through the TCA cycle with increased synthesis of serine, glycine, and glutathione. We also used single-cell RNA sequencing to compare the responses of individual cell types in NdpKO retinas with those in the hypoxic cerebral cortex of mice that were housed for 1 week in a reduced oxygen environment (7.5% oxygen). In the hypoxic cerebral cortex, glial transcriptome responses most closely resemble the response of Muller glia in the NdpKO retina. In both retina and brain, vascular endothelial cells activate a previously dormant tip cell gene expression program, which likely underlies the adaptive neoangiogenic response to chronic hypoxia. These analyses of retina and brain transcriptomes at single-cell resolution reveal both shared and cell type-specific changes in gene expression in response to chronic hypoxia, implying both shared and distinct cell type-specific physiologic responses.

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Optical Coherence Tomography Angiography in Familial Exudative Vitreoretinopathy: Clinical Features and Phenotype-Genotype Correlation

Cited by 23 publications

References 38 publications

Next-Generation Sequencing in the Familial Exudative Vitreoretinopathy-Associated Rhegmatogenous Retinal Detachment

Next-Generation Sequencing in the Familial Exudative Vitreoretinopathy-Associated Rhegmatogenous Retinal Detachment

Phenotypic Spectrum of the Foveal Configuration and Foveal Avascular Zone in Patients With Alport Syndrome

Hypoxia tolerance in the Norrin-deficient retina and the chronically hypoxic brain studied at single-cell resolution

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