Mutations in LRP5, FZD4, TSPAN12, NDP, ZNF408, or KIF11 Genes Account for 38.7% of Chinese Patients With Familial Exudative Vitreoretinopathy

Rao, Feng-Qin; Cai, Xue‐Bi; Cheng, Feifei; Wan, Cheng; Fang, Xiaolong; Li, Na; Huang, Xiu‐Feng; Li, Lihong; Jin, Zi‐Bing

doi:10.1167/iovs.16-21324

Cited by 61 publications

(67 citation statements)

References 26 publications

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“…The frequency of LRP5 mutations ranged from 10% to 22.2%, 18,25-28 TSPAN12 mutations were identified 2% to 10% in patients with autosomal dominant or autosomal recessive FEVR, 2,3,25,26,[28][29][30][31][32] while the frequency of NDP mutations ranges from 6.5% to 12.5%. 19,25,28,33,34 FEVR in Han Chinese may have a unique mutation spectrum with a larger involvement of FZD4, instead of LRP5.…”

Section: Discussionmentioning

confidence: 99%

Mutation Spectrum of the LRP5, NDP, and TSPAN12 Genes in Chinese Patients With Familial Exudative Vitreoretinopathy

Tang

Sun

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. LRP5, NDP, and TSPAN12 are known to be associated with familial exudative vitreoretinopathy (FEVR). In this study, a comprehensive mutation screening for the three genes was performed in patients with a clinical diagnosis of FEVR in Han Chinese.METHODS. Genomic DNA and clinical data were collected from 100 probands and their family members. Sanger sequencing was performed to screen for LRP5, NDP, and TSPAN12 mutations and phenotype-genotype correlation was analyzed.RESULTS. There were 23 causative mutations identified in 23 unrelated probands (10/23 in LRP5, 8/23 in TSPAN12, and 5/23 in NDP). Apart from NDP mutations, only two LRP5 mutations inherited in an autosomal recessive manner. Among the 23 causative mutations, 13 were novel variants (4/10 in LRP5, 6/8 in TSPAN12, and 3/5 in NDP). According to the modified classification system, statistical significance was observed in the distribution of mutated genes (P ¼ 0.049). None of the causative mutations was found in group I FEVR. Probands with LRP5 or NDP mutations were mainly categorized into group III and IV, TSPAN12 mutations were mainly observed in probands with group IV and V FEVR.CONCLUSIONS. The detection rate for mutations in the three known genes was 23%. Mutations in LRP5 and TSPAN12 were more frequent, accounting for 10% and 8%, respectively. The NDP mutations were only identified in 6% in this cohort. There were 13 novel variants found, which provided a deeper understanding of this disease. Potential phenotype-genotype correlation was observed in the modified system. TSPAN12 mutations might lead to the most severe phenotype.

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Section: Discussionmentioning

confidence: 99%

Mutation Spectrum of the LRP5, NDP, and TSPAN12 Genes in Chinese Patients With Familial Exudative Vitreoretinopathy

Tang

Sun

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Our prior study showed that the first four genes associated with the Wnt pathway accounted for about 44% of classical FEVR probands with a broad spectrum of phenotypes. 9,19 Similarly, Salvo et al 13 and Rao et al 20 reported that mutations in the six genes account for 48.9% and 38.7% of FEVR patients, respectively. Furthermore, the reported mutation frequencies in the LRP5, TSPAN12, and FZD4 genes varied a lot across different populations.…”

Section: Discussionmentioning

confidence: 98%

“…For example, the identification of LRP5 mutations was approximately 10% to 16.1% in China and approximately 19.6% in the United States. 12,13,20,21 FZD4 accounted for approximately 20% (8/40) in the United Kingdom 22 and approximately 14% in the United States. 13,23 TSPAN12 mutations accounted for approximately 8% of patients with FEVR in the United States, 13 and approximately 3.2% to 8% in different studies in the Chinese.…”

Section: Discussionmentioning

confidence: 99%

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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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“…In different studies of FEVR genes in Chinese pedigrees, the detection rates were variable; but did not exceed 50% [6,7]. Norrin/ frizzled signaling is critical for retinal angiogenesis by controlling retinal vascular growth and architecture both in developing eyes and in adult vasculature; impairment of this signaling pathway has profound effects on retinal vascular organization and leads to severe vascular abnormalities [8,9].…”

Section: Introductionmentioning

confidence: 99%

A Novel Variant of the FZD4 Gene in a Chinese Family Causes Autosomal Dominant Familial Exudative Vitreoretinopathy

Yang

Cheng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Familial exudative vitreoretinopathy (FEVR) is a complex hereditary eye disorder characterized by incomplete development of the retinal vasculature, thereby affecting retinal angiogenesis. Methods: In this study, a Chinese autosomal dominant FEVR pedigree was recruited. Ophthalmic examinations were performed, targeted next-generation sequencing was used to identify the causative gene, and Sanger sequencing was conducted to verify the candidate mutation. Co-segregation analysis was performed to evaluate pathogenicity. Semi-quantitative reverse transcription-PCR was applied to investigate the spatial and temporal expression patterns of the frizzled class receptor 4 (FZD4) gene in the mouse. Results: A novel heterozygous, deleterious variant of the FZD4 gene, c.A749G (p.Y250C), was identified in this FEVR pedigree, which co-segregated with the clinical phenotype. The amino acid tyrosine (Y) is highly conserved both orthologously and paralogously. The FZD4 gene was highly expressed in the retina, sclera of the eye, ovary, kidney, and liver; ubiquitously expressed in other tissues; and highly expressed in 6 different developmental stages/times of retinal tissue. Conclusion: Our study is the first to identify that the novel heterozygous variant c.A749G (p.Y250C) in the FZD4 gene may be the disease-causing mutation in this FEVR family, extending its mutation spectrum. These findings further our understanding of the molecular pathogenesis of FEVR and will facilitate the development of methods for the diagnosis, prevention, and genetic counseling of this disease.

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Mutations in LRP5, FZD4, TSPAN12, NDP, ZNF408, or KIF11 Genes Account for 38.7% of Chinese Patients With Familial Exudative Vitreoretinopathy

Cited by 61 publications

References 26 publications

Mutation Spectrum of the LRP5, NDP, and TSPAN12 Genes in Chinese Patients With Familial Exudative Vitreoretinopathy

Mutation Spectrum of the LRP5, NDP, and TSPAN12 Genes in Chinese Patients With Familial Exudative Vitreoretinopathy

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

A Novel Variant of the FZD4 Gene in a Chinese Family Causes Autosomal Dominant Familial Exudative Vitreoretinopathy

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