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Retina  |   June 2019
Next-Generation Sequencing in the Familial Exudative Vitreoretinopathy-Associated Rhegmatogenous Retinal Detachment
Author Affiliations & Notes
  • Chonglin Chen
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, SunYat-Sen University, Guangzhou, China
  • Zhirong Wang
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, SunYat-Sen University, Guangzhou, China
  • Limei Sun
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, SunYat-Sen University, Guangzhou, China
  • Sijian Huang
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, SunYat-Sen University, Guangzhou, China
  • Songshan Li
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, SunYat-Sen University, Guangzhou, China
  • Aiyuan Zhang
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, SunYat-Sen University, Guangzhou, China
  • Xiaoling Luo
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, SunYat-Sen University, Guangzhou, China
  • Li Huang
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, SunYat-Sen University, Guangzhou, China
  • Xiaoyan Ding
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, SunYat-Sen University, Guangzhou, China
  • Correspondence: Xiaoyan Ding, State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, SunYat-Sen University, Guangzhou, 510060, China; dingxiaoyan@gzzoc.com
  • Footnotes
     CC and ZW contributed equally to the work presented here and should therefore be regarded as equivalent authors.
Investigative Ophthalmology & Visual Science June 2019, Vol.60, 2659-2666. doi:https://doi.org/10.1167/iovs.19-26619
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      Chonglin Chen, Zhirong Wang, Limei Sun, Sijian Huang, Songshan Li, Aiyuan Zhang, Xiaoling Luo, Li Huang, Xiaoyan Ding; Next-Generation Sequencing in the Familial Exudative Vitreoretinopathy-Associated Rhegmatogenous Retinal Detachment. Invest. Ophthalmol. Vis. Sci. 2019;60(7):2659-2666. doi: https://doi.org/10.1167/iovs.19-26619.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: 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.

First described by Criswick and Schepens in 1969,1 familial exudative vitreoretinopathy (FEVR) is a hereditary disorder affecting retinal angiogenesis. Clinical findings include abnormalities in the vitreous composition and vitreoretinal interface, peripheral avascular retina, abnormal retinal vasculature, including late-phase angiographic posterior and peripheral leakage (LAPPEL) and extraretinal neovascularization (ERNV), subretinal exudates, and retinal detachments, most commonly tractional or exudative. Recently, several reports have identified FEVR as one of the causes of rhegmatogenous retinal detachment (RRD), especially in young patients.24 Our previous study analyzed the age, sex, and clinical features of the affected and fellow eyes of FEVR-RRD patients,5 but the genetic characteristics of this disease remain unknown. 
To date, six genes have been reported to be responsible for this disease, including low-density lipoprotein receptor related protein 5 (LRP5), frizzled-4 (FZD4), tetraspanin-12 (TSPAN12), Norrie disease protein (NDP), kinesin family member 11(KIF11), and zinc finger protein 408 (ZNF408). Proteins encoded by the first four genes are involved in the Wnt/Norrin signaling pathway, and they play crucial roles in retinal vasculature development and angiogenesis. Mutations in KIF11 are reported to be involved in microcephaly, chorioretinopathy, and mental retardation. Recently, Robitaille et al.6 reported that KIF11 mutations were identified in patients with FEVR. Mutation in ZNF408 was reported to be a novel cause of FEVR by Collin7; however, the evidence has not been confirmed. In this study, these six genes were tested in patients with clinically diagnosed FEVR-RRD, and the preliminary genotype–phenotype correlation was analyzed. 
Materials and Methods
This cross-sectional study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Zhongshan Ophthalmic Center, Sun Yat-sen University. This study enrolled 54 patients with FEVR-RRD who received surgery between July 2016 and June 2018. A comprehensive ophthalmic examination was performed, including slit-lamp biomicroscopy, binocular indirect ophthalmoscopy, IOP measurement, fundus photographs, and fundus fluorescein angiography (FFA). The peripheral retina of the affected and fellow eyes was checked carefully under mydriatic conditions with a Goldman three-mirror contact lens to confirm that retinal breaks were responsible for the retinal detachment. The first-degree relatives of the patients were screened in most of the families (45/54). The inclusion criteria were as follows. (1) The diagnosis of FEVR was determined by funduscopy and FFA in fellow eyes in accordance with previous studies.5,8 Peripheral avascular areas, extensive branching, or dragging of the vessels in fellow eyes was required in unilateral RRD patients. (2) A positive family history of diagnosed FEVR was required in bilateral RRD patients. Patients with premature delivery (<37 gestational weeks), low neonatal birth weight (<2500 g), history of ocular trauma, uveitis, surgery, or cryotherapy, or collagen vascular diseases were excluded. Forty-six ethnically matched regular RRD patients without history of any other ocular diseases were recruited as controls. 
In our study, gene tests on these six known genes were performed in all patients. All DNA samples were extracted from peripheral whole-blood samples. Targeted next-generation sequencing was performed using a custom genetic pediatric retinal disease panel.9 Identified mutation was validated by Sanger sequencing through family members. All coding sequences and intron–exon junctions were amplified and sequenced comprehensively, followed by cosegregation testing to verify suspected variants in the family members. The Human Gene Mutation Database, ExAC databases, dbSNP, and gnomeAD were consulted to identify reported pathogenic variants. Online algorithms, including PolyPhen2, Mutation Taster, and PROVEAN, were used to estimate the pathogenicity of the missense changes. Family segregation was also studied. 
Statistical Analysis
All statistical analyses were performed using SPSS (Statistical Product and Service Solutions, Version 22.0; IBM Corporation, Chicago, IL, USA). The average age and sex were analyzed using an independent-samples t-test or Fisher's exact test. The clinical features of the fellow eyes were analyzed using frequency and descriptive statistics. P < 0.05 was considered statistically significant. 
Results
A total of 54 patients with FEVR-RRD were included in this study. The average age was 21.9 ± 10.9 years (range, 4–50 years old), and 77.8% (42/54) of the participants were under 30 years old in the FEVR-RRD group. In the control group, the average age was 41.5 ± 16.0 years (range, 16–70 years old; P = 0.001), and only 34.8% (16/46) patients were under 30 years old. The male-to-female ratio was 2.2:1 (37:17) in the FEVR-RRD group. The average age of male participants (19.0 ± 10.0 years) was younger than that of female participants (28.4 ± 10.2 years, P = 0.002). A total of 48.6% (18/37) of male patients were 11 to 20 years old, whereas only 23.5% (4/17) of female patients were 11 to 20 years old (P = 0.072). However, 41.2% (7/17) of female patients were 21 to 30 years old (Table 1). The percentages of patients with proliferative vitreoretinopathy (PVR) ≥ grade C were not different significantly between the FEVR-RRD and control groups (P = 0.106). 
Table 1
 
Age and Sex of FEVR-RRD Patients (n = 54)
Table 1
 
Age and Sex of FEVR-RRD Patients (n = 54)
Mutations in LRP5, FZD4, and TSPAN12 Genes Account for 38.9% of FEVR-RRD Patients
All patients received genetic tests. Causative mutations were identified in 38.9% (21/54) of patients, including LRP5 mutations in 14 patients, FDZ4 mutations in 4 patients, and TSPAN12 mutations in 3 patients (Fig. 1). Among the 21 individuals with causative mutations, 13 had a positive familial history of FEVR, and 8 were sporadic cases. Schematic pedigrees of the families with causative mutations are shown in Figure 2. In the current study, 22 potentially pathogenic mutations were identified in 21 unrelated FEVR probands, including 1 patient harboring compound heterozygous mutations in LRP5 (1330C>T; 3913T>C) and 2 unrelated individuals carrying the same reported FZD4 mutation (1589G>A). None of these novel mutations were detected in 46 ethnically matched control subjects. Among these 22 variants, 14 were novel (10/15 in LRP5, 1/4 in FZD4, and 3/3 in TSPAN12). These variants were not found in current online databases of human sequence variants, including the Human Gene Mutation Database, ExAC databases, dbSNP, and gnomeAD (Table 2). 
Figure 1
 
Mutation spectrum in Chinese patients with FEVR-RRD. LRP5, FDZ4, or TSPAN12 mutations were noted in 21/54 (38.9%) patients, whereas no known gene mutations were identified in 33/54 (61.1%) patients. LRP5, FDZ4, and TSPAN12 mutations were noted in 14/54 (25.9%) patients, 4/54 (7.4%) patients, and 3/54 (5.6%) patients, respectively.
Figure 1
 
Mutation spectrum in Chinese patients with FEVR-RRD. LRP5, FDZ4, or TSPAN12 mutations were noted in 21/54 (38.9%) patients, whereas no known gene mutations were identified in 33/54 (61.1%) patients. LRP5, FDZ4, and TSPAN12 mutations were noted in 14/54 (25.9%) patients, 4/54 (7.4%) patients, and 3/54 (5.6%) patients, respectively.
Figure 2
 
Schematic pedigrees of the families with causative mutations. Arrows indicate proband (with FEVR-RRD); open symbols, clinically unaffected; solid symbols, clinically affected; +, clinically evaluated; +/+, homozygous mutation; +/−, heterozygous mutation; −/−, wild type.
Figure 2
 
Schematic pedigrees of the families with causative mutations. Arrows indicate proband (with FEVR-RRD); open symbols, clinically unaffected; solid symbols, clinically affected; +, clinically evaluated; +/+, homozygous mutation; +/−, heterozygous mutation; −/−, wild type.
Table 2
 
Causative Mutations Identified in 54 Probands With FEVR-RRD
Table 2
 
Causative Mutations Identified in 54 Probands With FEVR-RRD
Characteristics of the Affected and Fellow Eyes in FEVR-RRD Patients
RRD history in the fellow eyes was identified in one patient. Thus, a total of 55 eyes were considered affected eyes, and the remaining 53 eyes were grouped as fellow eyes without RRD. Retinal holes were located in the superior temporal quadrant in 33/55 (60%) affected eyes, in the inferior temporal quadrant in 21/55 (38.2%) affected eyes, and at the nasal quadrant in 1/55 (1.8%) affected eyes. 
The characteristics of the 53 fellow eyes are summarized in Table 3 and Figure 3. LAPPEL, which was the most frequent abnormality, was shown in 39 (73.6%) eyes. Lattice degeneration, located at the margin of the temporal peripheral avascular area, was found in 28 (52.8%) eyes. ERNV was shown in 17 (32.1%) eyes. Other major manifestations, including extensive anastomosis, V-shape degeneration, peripheral retinal ridge, and macular dragging, were found in three (5.7%), six (11.3%), six (11.3%), and seven (13.2%) patients, respectively. 
Table 3
 
Characteristics of the Fellow Eyes in FEVR-RRD Patients (n = 53)
Table 3
 
Characteristics of the Fellow Eyes in FEVR-RRD Patients (n = 53)
Figure 3
 
Characteristics of the affected and fellow eyes of patients with FEVR-RRD. Representative images of retinal breaks from two FEVR-RRD patients are shown in A and B. Round retinal hole (green arrow) was identified in the superior temporal quadrant of the retina in the right eye of an 11-year-old boy (A). A 28-year-old male with a round retinal hole (white arrow) in the inferior temporal quadrant of the retina in his right eye (B). Characteristics of the fellow eyes of FEVR-RRD are shown in CF. Retinal ridge (yellow arrow, C), avascular zone and vascular leakage (red arrow, D), extensive anastomosis (blue arrow, E), and macular dragging (F) were found in the fellow eyes of FEVR-RRD patients.
Figure 3
 
Characteristics of the affected and fellow eyes of patients with FEVR-RRD. Representative images of retinal breaks from two FEVR-RRD patients are shown in A and B. Round retinal hole (green arrow) was identified in the superior temporal quadrant of the retina in the right eye of an 11-year-old boy (A). A 28-year-old male with a round retinal hole (white arrow) in the inferior temporal quadrant of the retina in his right eye (B). Characteristics of the fellow eyes of FEVR-RRD are shown in CF. Retinal ridge (yellow arrow, C), avascular zone and vascular leakage (red arrow, D), extensive anastomosis (blue arrow, E), and macular dragging (F) were found in the fellow eyes of FEVR-RRD patients.
The Genotype–Phenotype Association With Causative Mutations of the Fellow Eyes
After screening the coding and flanking regions of LRP5, FZD4, and TSPAN12 for mutations, among the 22 causative mutations of the FEVR patients, 42.9% (6/14) of patients with LRP5 mutations had LAPPEL. Of patients with FZD4 mutations or TSPAN12 mutations 100% (7/7; 4/4 with FZD4 mutations and 3/3 with TSPAN12 mutations) had LAPPEL (P = 0.018; Table 4; Fig. 4). Of patients with LRP5 mutations, 21.4% (3/14) had ERNV. However, 85.7% (6/7) of patients with FZD4 mutations or TSPAN12 mutations (4/4 patients with FZD4 mutations and 2/3 patients with TSPAN12 mutations) had ERNV (P = 0.016; Table 5; Fig. 4). 
Table 4
 
LAPPEL in Patients With Causative LRP5, FZD4, and TSPAN12 Mutations
Table 4
 
LAPPEL in Patients With Causative LRP5, FZD4, and TSPAN12 Mutations
Figure 4
 
Genotype–phenotype correlation in patients with FEVR-RRD. LAPPEL was noted mainly in patients with FZD4 (4/4) or TSPAN12 (3/3) mutations, but only in 6/14 patients with LRP5 mutations. ERNV was noted 4/4 patients with FZD4 mutations and 2/3 patients with TSPAN12 mutations, but only in 3/14 patients with LRP5 mutations.
Figure 4
 
Genotype–phenotype correlation in patients with FEVR-RRD. LAPPEL was noted mainly in patients with FZD4 (4/4) or TSPAN12 (3/3) mutations, but only in 6/14 patients with LRP5 mutations. ERNV was noted 4/4 patients with FZD4 mutations and 2/3 patients with TSPAN12 mutations, but only in 3/14 patients with LRP5 mutations.
Table 5
 
ERVN in Patients With Causative LRP5, FZD4, and TSPAN12 Mutations
Table 5
 
ERVN in Patients With Causative LRP5, FZD4, and TSPAN12 Mutations
Representative Clinical Findings in Patients With Causative Mutations
The novel LRP5 mutation of nucleotide 4046-4048del was harbored in a 4-year-old boy who exhibited bilateral retinal detachment. The single base pair deletion was predicted to cause a protein change of 1349-1350del. His father, who had typical FEVR manifestation of extensive anastomosis, LAPPEL, and straightening vessel branching in the peripheral retina in both eyes, carried the same mutation. His healthy mother did not carry the same mutation (Fig. 5). 
Figure 5
 
Representative clinical findings in patients with causative LRP5 mutation. The novel LRP5 mutation of nucleotide 4046-4048del, which was predicted to cause a protein change of 1349-1350del, was identified in a 4-year-old boy. His father, who had a typical FEVR manifestation, carried the same mutation, but his healthy mother did not carry the same mutation (A). FFA showed that the proband exhibited bilateral retinal detachment (B). Ultrasonography showed that the retina was detached in both eyes (C). FFA showed that the father had extensive anastomosis (blue arrow) in his right eye, lattice degeneration (purple arrow) in his left eye, and peripheral leakage (red arrow) and straightening vessel branching in the peripheral retina in both eyes (D).
Figure 5
 
Representative clinical findings in patients with causative LRP5 mutation. The novel LRP5 mutation of nucleotide 4046-4048del, which was predicted to cause a protein change of 1349-1350del, was identified in a 4-year-old boy. His father, who had a typical FEVR manifestation, carried the same mutation, but his healthy mother did not carry the same mutation (A). FFA showed that the proband exhibited bilateral retinal detachment (B). Ultrasonography showed that the retina was detached in both eyes (C). FFA showed that the father had extensive anastomosis (blue arrow) in his right eye, lattice degeneration (purple arrow) in his left eye, and peripheral leakage (red arrow) and straightening vessel branching in the peripheral retina in both eyes (D).
Discussion
It is well documented that tractional retinal detachment (TRD) and exudative retinal detachment (ERD) are typically considered the end stage of severe FEVR, in which complications may develop earlier in life. However, the association between RRD and FEVR is not yet confirmed. RRD is uncommon in the pediatric population, and most patients have predisposing factors such as trauma, myopia, and congenital or developmental anomalies.1518 Previously, a few reports have suggested FEVR as one of the causes of RRD, although the causality is still unknown.25 In the current study, we performed a cross-sectional study focusing on not only the clinical but also the genetic characteristics of FEVR-RRD. To the best of our knowledge, our results identify for the first time the genetic profiles of patients clinically diagnosed with FEVR-RRD. 
Thus far, six genes LRP5, FZD4, TSPAN12, NDP, KIF11, and ZNF408 were known to be responsible for about less than half of the FEVR patients. 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. 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 Kingdom22 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.9,20 Notably, no FEVR-RRD patients were included in any of these previous studies. 
In our study, causative mutations were identified in 38.9% (21/54) of FEVR-RRD patients, including LRP5 mutations in 25.9% (14/54) of patients, FDZ4 mutations in 7.4% (4/54) of patients, and TSPAN12 mutations in 5.6% (3/54) patients. Our study provides several important pieces of evidence. First, our results showed that FEVR-RRD has a pathologic genetic background similar to that of classical FEVR, which suggests that RRD should be considered a novel phenotype of FEVR. This disease entity is actually due to (not only associated with) FEVR. These patients have typical clinical features of FEVR in the fellow eyes, which may indicate the phenotype in the affected eyes before retinal detachment occurred. The typical features included an abrupt termination of the retinal capillary network and extensive branching. The phenotype of FEVR-RRD is the same, or at least similar, to that of typical traditional FEVR. 
Second, our study expanded clinical spectrum of retinal detachment in FEVR. TRD and ERD were typically present in severe cases or patients with end stage FEVR. In this study, the average age of FEVR-RRD patients was 21.9 ± 10.9 years old. Although 77.8% of the participants were younger than 30 years old, the average age is much older than the onset age of TRD/ERD. Most of the fellow eyes had normal visual functions. Thus, we suggested that RRD, in contrast to TRD and ERD, should be considered a mild phenotype of FEVR, which lies on the left side of the broad spectrum of dramatically variant phenotype spectrum. 
Third, the preliminary genotype–phenotype correlation was also analyzed in this cohort of individuals. Different from the genetic profile in the classical FEVR population, LRP5 mutations are the leading cause of FEVR-RRD. The fellow eyes with LRP5 mutations in our series were more likely to have milder retinal vascular abnormalities compared with those with FZD4 or TSPAN12 mutation. 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 genotype–phenotype 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. Similarly, 41.7% (5/12) of causative genes were missense variants in the report of Rao et al.20 and 65.3% (32/49) in the report of Salvo et al.13 We believe that RRD should be considered as a common, independent clinical feature of FEVR, which may be seriously underdiagnosed in clinical practice. 
The limitations of our study are as follows. First, despite the relatively large sample size, FEVR is a rare disease, and the number of patients is limited. Second, because our center is a tertiary referral hospital for pediatric vitreoretinal diseases, referral bias could be present. Third, cultural or social factors may affect family decision making, which may introduce unpredicted bias. 
In conclusion, to the best of our knowledge, this is the first study to focus on the genotype of FEVR-RRD. Our results confirmed that this novel phenotype is most likely due to FEVR, which has a genetic background similar to that of other traditional FEVR patients. However, the six known genes explained 38.9% of patients with FEVR-RRD, indicating that there are other genes or factors underlying the etiology of FEVR-RRD, which deserves further investigation. Furthermore, our study's preliminary analysis indicated that RRD is a relatively mild phenotype in the entire phenotype spectrum of FEVR. 
Acknowledgments
Supported by grants from the Fundamental Research Funds of State Key Laboratory of Ophthalmology, research funds of Sun Yat-sen University (Grant 15ykjc22d), the Science and Technology Program (Grant 201803010031), and the Medical Scientific Research Foundation of Guangdong Province (Grant 2016118152947764). 
Disclosure: C. Chen, None; Z. Wang, None; L. Sun, None; S. Huang, None; S. Li, None; A. Zhang, None; X. Luo, None; L. Huang, None; X. Ding, None 
References
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Figure 1
 
Mutation spectrum in Chinese patients with FEVR-RRD. LRP5, FDZ4, or TSPAN12 mutations were noted in 21/54 (38.9%) patients, whereas no known gene mutations were identified in 33/54 (61.1%) patients. LRP5, FDZ4, and TSPAN12 mutations were noted in 14/54 (25.9%) patients, 4/54 (7.4%) patients, and 3/54 (5.6%) patients, respectively.
Figure 1
 
Mutation spectrum in Chinese patients with FEVR-RRD. LRP5, FDZ4, or TSPAN12 mutations were noted in 21/54 (38.9%) patients, whereas no known gene mutations were identified in 33/54 (61.1%) patients. LRP5, FDZ4, and TSPAN12 mutations were noted in 14/54 (25.9%) patients, 4/54 (7.4%) patients, and 3/54 (5.6%) patients, respectively.
Figure 2
 
Schematic pedigrees of the families with causative mutations. Arrows indicate proband (with FEVR-RRD); open symbols, clinically unaffected; solid symbols, clinically affected; +, clinically evaluated; +/+, homozygous mutation; +/−, heterozygous mutation; −/−, wild type.
Figure 2
 
Schematic pedigrees of the families with causative mutations. Arrows indicate proband (with FEVR-RRD); open symbols, clinically unaffected; solid symbols, clinically affected; +, clinically evaluated; +/+, homozygous mutation; +/−, heterozygous mutation; −/−, wild type.
Figure 3
 
Characteristics of the affected and fellow eyes of patients with FEVR-RRD. Representative images of retinal breaks from two FEVR-RRD patients are shown in A and B. Round retinal hole (green arrow) was identified in the superior temporal quadrant of the retina in the right eye of an 11-year-old boy (A). A 28-year-old male with a round retinal hole (white arrow) in the inferior temporal quadrant of the retina in his right eye (B). Characteristics of the fellow eyes of FEVR-RRD are shown in CF. Retinal ridge (yellow arrow, C), avascular zone and vascular leakage (red arrow, D), extensive anastomosis (blue arrow, E), and macular dragging (F) were found in the fellow eyes of FEVR-RRD patients.
Figure 3
 
Characteristics of the affected and fellow eyes of patients with FEVR-RRD. Representative images of retinal breaks from two FEVR-RRD patients are shown in A and B. Round retinal hole (green arrow) was identified in the superior temporal quadrant of the retina in the right eye of an 11-year-old boy (A). A 28-year-old male with a round retinal hole (white arrow) in the inferior temporal quadrant of the retina in his right eye (B). Characteristics of the fellow eyes of FEVR-RRD are shown in CF. Retinal ridge (yellow arrow, C), avascular zone and vascular leakage (red arrow, D), extensive anastomosis (blue arrow, E), and macular dragging (F) were found in the fellow eyes of FEVR-RRD patients.
Figure 4
 
Genotype–phenotype correlation in patients with FEVR-RRD. LAPPEL was noted mainly in patients with FZD4 (4/4) or TSPAN12 (3/3) mutations, but only in 6/14 patients with LRP5 mutations. ERNV was noted 4/4 patients with FZD4 mutations and 2/3 patients with TSPAN12 mutations, but only in 3/14 patients with LRP5 mutations.
Figure 4
 
Genotype–phenotype correlation in patients with FEVR-RRD. LAPPEL was noted mainly in patients with FZD4 (4/4) or TSPAN12 (3/3) mutations, but only in 6/14 patients with LRP5 mutations. ERNV was noted 4/4 patients with FZD4 mutations and 2/3 patients with TSPAN12 mutations, but only in 3/14 patients with LRP5 mutations.
Figure 5
 
Representative clinical findings in patients with causative LRP5 mutation. The novel LRP5 mutation of nucleotide 4046-4048del, which was predicted to cause a protein change of 1349-1350del, was identified in a 4-year-old boy. His father, who had a typical FEVR manifestation, carried the same mutation, but his healthy mother did not carry the same mutation (A). FFA showed that the proband exhibited bilateral retinal detachment (B). Ultrasonography showed that the retina was detached in both eyes (C). FFA showed that the father had extensive anastomosis (blue arrow) in his right eye, lattice degeneration (purple arrow) in his left eye, and peripheral leakage (red arrow) and straightening vessel branching in the peripheral retina in both eyes (D).
Figure 5
 
Representative clinical findings in patients with causative LRP5 mutation. The novel LRP5 mutation of nucleotide 4046-4048del, which was predicted to cause a protein change of 1349-1350del, was identified in a 4-year-old boy. His father, who had a typical FEVR manifestation, carried the same mutation, but his healthy mother did not carry the same mutation (A). FFA showed that the proband exhibited bilateral retinal detachment (B). Ultrasonography showed that the retina was detached in both eyes (C). FFA showed that the father had extensive anastomosis (blue arrow) in his right eye, lattice degeneration (purple arrow) in his left eye, and peripheral leakage (red arrow) and straightening vessel branching in the peripheral retina in both eyes (D).
Table 1
 
Age and Sex of FEVR-RRD Patients (n = 54)
Table 1
 
Age and Sex of FEVR-RRD Patients (n = 54)
Table 2
 
Causative Mutations Identified in 54 Probands With FEVR-RRD
Table 2
 
Causative Mutations Identified in 54 Probands With FEVR-RRD
Table 3
 
Characteristics of the Fellow Eyes in FEVR-RRD Patients (n = 53)
Table 3
 
Characteristics of the Fellow Eyes in FEVR-RRD Patients (n = 53)
Table 4
 
LAPPEL in Patients With Causative LRP5, FZD4, and TSPAN12 Mutations
Table 4
 
LAPPEL in Patients With Causative LRP5, FZD4, and TSPAN12 Mutations
Table 5
 
ERVN in Patients With Causative LRP5, FZD4, and TSPAN12 Mutations
Table 5
 
ERVN in Patients With Causative LRP5, FZD4, and TSPAN12 Mutations
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