Abstract
The aim is to explore the LRP5 gene frequencies in infants with familial exudative vitreoretinopathy (FEVR) phenotype in Chongqing and Urumqi. This study enrolled a group of infants in Chongqing and Urumqi diagnosed with the FEVR phenotype during neonatal eye disease screening. The infants were stratified by sex and ethnicity. Blood samples from the infants and their parents were collected for genetic testing, and the correlations between the incidence of FEVR and LRP5 status were examined using the χ2 test. There was no significant difference in the mutation rate of LRP5 between the 2 regions (P = .664). Among the patients carrying LRP5 mutations, there was no statistically significant difference in terms of sex (P = 1.0) and ethnicity (P = .386). Among the LRP5-mutated infants in Chongqing, 1 carried 2 different mutations and 15 carried 1 mutation. Among the LRP5-mutated infants in Urumqi, 1 carried 3 different mutations. Among patients with LRP5 mutations, 22.22% had unilateral disease, 9.38% of patients were diagnosed at stage 1A, 75% at stage 1B, 6.25% at stage 2A, and 9.38% at stage 2B. No stage 3, 4, or 5 patients were included in the study. About 6.25% of patients experienced retinal hemorrhage, 3.13% reported lens opacity, and 3.13% reported morning glory syndrome. In conclusion, no reliable correlations were found between the mutation rate of LRP5 and geographic, regional, or sex factors. Carriers of multiple gene mutations along with LRP5 mutations are more likely to develop more severe phenotypes than carriers of only LRP5 mutations.
Keywords: familial exudative vitreoretinopathy, genotype, LRP5, phenotype
1. Introduction
Patients with familial exudative vitreoretinopathy (FEVR) collectively represent a wide range of genotypes and phenotypes, and no reliable genotype–phenotype correlations have been found. Patients from different families, the same family, or both eyes of the same patient could manifest different clinical symptoms. To date, 11 genes have been identified as pathogenic for FEVR, including NDP, FZD4, LRP5, TSPAN12, ZNF408, KIF11, RCBTB1, CTNNB, JAG1, EVR3, and ATOH7,[1] and in which a 2017[2] study showed LRP5 mutations accounted for 42% and were the most frequent of all mutation types in Chinese FEVR patients. Chen et al[3] discovered that compared to patients with FDZ4 or TSPAN12 mutations, patients with LRP5 mutations tend to be associated with less severe phenotypes. In clinical practice, FEVR patients with this mutation need to be screened for osteoporosis-pseudoglioma syndrome, which could lead to blindness and decreased bone density. Patients usually present during their neonatal period and have an early onset of other symptoms during their childhoods. A recent cohort study of 34 families with a history found LRP5 mutations were the most dominant in families in which both parents carried related gene mutations, accounting for up to 64.61%. This was followed by FZD4 (12.31%), NDP (10.77%), TSPAN12 (6.15%), ZNF408 (4.62%), and KIF11 (1.54%) mutations.[4]
The LRP5 gene is located on chromosome 11q13.2 and encodes a transmembrane protein of 1615 amino acids, which is a member of the low-density lipoprotein receptor family. More than 80 mutation sites have been reported in this gene, which can lead to autosomal dominant or recessive FEVR. The LRP5 protein consists of an extracellular domain, transmembrane domain, and cytoplasmic domain. The LRP5 protein can jointly bind to Wnts or Norrin with the FZD4 protein to form a functional ligand-receptor complex, which triggers the Wnt/β-catenin or Norrin/β-catenin pathway and consequently induces the transcription of the target gene.[5] This synergistic effect of 2 separate pathogenic genes of FEVR[6] indicates that FEVR could develop variable phenotypes among patients from the same family or in the 2 eyes of 1 patient. In another study, 2 patients developed more serious symptoms than their parents.[7] These findings suggest that FEVR may not be a single-gene hereditary disease but a hereditary disease with complex genetic causes, which could be 1 of the reasons why FEVR patients may experience clinical signs of variable severity.
2. Materials and methods
2.1. Subjects
The subjects of the study were selected from patients diagnosed with FEVR during neonatal eye disease screening at Chongqing Maternal and Child Health Hospital at Urumqi Maternal and Child Health Hospital in Urumqi. Blood samples were collected from the subjects and their parents with signed written consent from the subjects’ guardians who agreed to the collection on a voluntary basis, in accordance with the Declaration of Helsinki and the relevant guidelines for the collection of human genetic disease specimens released by the Ministry of Health of China. Venous blood (2 mL) was drawn from each infant and their parents and stored at −80 °C. Ethics approval and informed consent to participate were obtained from participants (their parents or legal guardians in the case of children under 16) for participation in this study and to publish the study findings. Ethical aspects of the studies and procedures related to clinical examination, human sample collection, and genetic analysis were approved by the Medical Ethics Committee of the Chongqing Health Center for Women and Children and Urumqi Health Center for Women and Children. All methods were performed in accordance with the relevant guidelines and regulations of the Declaration of Helsinki. Ethical review number: (2018) No. 012.
2.2. Screening
The parents were informed of the screening precautions and signed informed consent letters for neonatal eye screenings. Details regarding the newborns’ sex, birth weight, gestational age, mode of delivery, mother’s age, maternal parity, and whether the mother had any diseases during pregnancy were collected. Fundus examinations were performed using RetCam 3 Wide-Field Digital Imaging System produced by (Clarity, Pleasanton).
2.3. Diagnosis
All diagnoses were made by experienced ophthalmologists specializing in fundus diseases based on the condition of the newborn’s eyes. FEVRs are staged using an approach similar to retinopathy of prematurity staging. Pendergast and Trese divided FEVR into 5 stages: stage 1, avascular zone present in the peripheral retina but without neovascularization; stage 2, avascular zone in the peripheral retina with neovascularization; stage 3, macular-sparing subtotal retinal detachment; stage 4, macular-on subtotal retinal detachment; stage 5, total retinal detachment, open or closed funnel-shaped. Additionally, stages 2–5 can be further categorized as nonexudative A and exudative B stages.[8] Retinal zones are defined as follows: zone 1 is centered on the optic disc and extends to the area where the major retinal vessels emerge; zone 2 encompasses the area from the edge of zone 1 to the equator of the eye; and zone 3 includes the peripheral retina extending from the edge of zone 2 to the ora serrata.[9]
2.4. Statistical methods
Statistical analyses were conducted using Statistical Product and Service Solutions (SPSS), Version 20.0; IBM Corporation, Chicago, and all numerical values were converted to percentages (%). The differences in LRP5 mutation frequency among FEVR patients from different regions were examined using the χ2 test. If the theoretical frequency was >5, a Pearson χ2 test was performed. If the theoretical frequency was between 1 and 5, a continuity-corrected χ2 test was performed. If the theoretical frequency was <1, Fisher exact test was performed. Statistical significance was defined as P < .05.
3. Results
3.1. LRP5 mutations in Chongqing and Urumqi
Among the 90 probands in Chongqing, 39 subjects (43.33%) were identified as carriers of FEVR pathogenic gene mutations, including 18 carriers (20%) of LRP5 mutations. Among the LPR5-mutated subjects, 12 were male and 6 were female; by ethnicity, 16 were of Han ethnicity, 1 was of Miao ethnicity, and 1 was of Tujia ethnicity.
Among the 16 probands in Urumqi, 6 subjects (37.5%) were carriers of FEVR pathogenic gene mutations, including 3 carriers (18.75%) of LRP5 mutations. Among the LPR5-mutated subjects, 2 were male and 1 was female; by ethnicity,2 were of Han ethnicity and 1 was of Hui ethnicity.
As shown in Table 1, there was no significant difference in the mutation rate of LRP5 between the 2 regions (P > .05). Among the patients carrying LRP5 mutations, there were no statistically significant differences in terms of sex and ethnicity (P > .05). The mutation types of the subjects from both regions were predominantly nonsynonymous single nucleotide variants, which accounted for 88.89% of all mutations in Chongqing and 100% in Urumqi (Table 2).
Table 1.
LRP5 mutations in Chongqing and Urumqi.
| Chongqing | Urumqi | χ 2 | P value | |
|---|---|---|---|---|
| Probands | 90 | 16 | ||
| Overall mutation frequency | 39 (43.33%) | 6 (37.5%) | 0.189 | .664 |
| LRP5 mutation frequency, n (%) | 18 (20%) | 3 (18.75%) | 0.013 | .908 |
| Sex | ||||
| Male | 12 (13.33%) | 2 (12.5%) | 0.000 | 1.000 |
| Female | 6 (6.67%) | 1 (6.25%) | ||
| Ethnicity | ||||
| Han | 16 (17.78%) | 2 (12.5%) | 1.037 | .386 |
| Minority | 2 (2.22%) | 1 (6.25%) |
Table 2.
LRP5 mutation type analysis.
| Region | Frameshift deletion | Frameshift insertion | Nonframeshift deletion | Nonframeshift insertion | Nonsynonymous SNV | Stopgain | Total |
|---|---|---|---|---|---|---|---|
| Chongqing | 0 | 0 | 1 | 0 | 16 | 1 | 18 |
| Urumqi | 0 | 0 | 0 | 0 | 3 | 0 | 3 |
SNV = single nucleotide variants.
3.1.1. LRP5 mutations in Chongqing
Among the 18 LRP5-mutated probands in Chongqing, 17 mutation sites were identified. One child carried 2 different mutations and 15 carried only 1 mutation. Two pairs of probands had identical mutation sites. Probands with identical LRP5 mutation sites inherited their mutations from their fathers. Among the 18 LRP5-mutated probands, 9 subjects (50%) carried paternal mutations, 7 (38.89%) carried maternal mutations, 1 (5.56%) carried parental mutations (both parents had LRP5 mutations, and the proband inherited the mutation homozygously), and 1 proband (5.56%) developed the mutation spontaneously (Tables 3 and 4).
Table 3.
LPR5 mutation sources in Chongqing and Urumqi.
| Paternal (n) | Maternal (n) | Parental (n) | Spontaneous (n) | |
|---|---|---|---|---|
| Chongqing | 9 | 7 | 1 | 1 |
| Urumqi | 0 | 2 | 1 | 0 |
Table 4.
LRP5 mutations sites in Chongqing probands.
| Mutation sites | Nucleotide changes | Amino acid changes | Variation | Subject no. |
|---|---|---|---|---|
| chr11-68177511 | c.A2221G | p.R741G | A-G | FEVR-010 |
| chr11-68154153 | c.G1385A | p.R462Q | G-A | FEVR-024 |
| chr11-68153898 | c.C1130T | p.A377V | C-T | FEVR-036 |
| chr11-68171037 | c.C1671A | p.F557L | C-A | FEVR-051 |
| chr11-68216333 | c.G4643T | p.C1548F | G-T | FEVR-052/FEVR-222 |
| chr11-68125147 | c.C518T | p.T173M | C-T | FEVR-095 |
| chr11-68204398 | c.T4042C | p.C1348R | T-C | FEVR-106 |
| chr11-68174175 | C1985T | p.T662I | C-T | FEVR-111 |
| chr11-68174186 | c.G1996A | p.D666N | G-A | FEVR-131 |
| chr11-68201207 | c.G3901A | p.A1301T | G-A | FEVR-154 |
| chr11-68080215- chr11-68080229 | c.33_47del | p.L16_L20del | GCTGCTGCT-del | FEVR-158 |
| chr11-68170999 | c.C1633T | p.L545F | C-T | FEVR-164 |
| chr11-68115513 | c.C290T | p.A97V | C-T | FEVR-167/FEVR-183 |
| chr11-68197061 | c.G3656A | p.R1219H | G-A | FEVR-234 |
| chr11-68183972 | c.C3004T | p.R1002X | C-T | FEVR-261 |
| chr11-68207355 | c.T4459G | p.S1487A | T-G | FEVR-291 |
Five infants (27.78%) were found to carry 2 mutations at the same time (Table 5).
Table 5.
Chongqing probands carrying 2 mutations including LRP5.
| Mutated gene | Mutation site | Nucleotide changes | Amino acid changes | Variation | Source | |
|---|---|---|---|---|---|---|
| FEVR-010 | LRP5 | chr11-68177511 | c.A2221G | p.R741G | A-G | Mother |
| ZNF408 | chr11-46726503 | c.A1253G | p.Y418C | A-G | Father | |
| FEVR-036 | LRP5 | chr11-68153898 | c.C1130T | p.A377V | C-T | Mother |
| SLC9A3 | Chr5-476492 | c.A1892G | p.Y631C | T-C | Father | |
| FEVR-95 | LRP5 | chr11-68125147 | c.C518T | p.T173M | C-T | Mother |
| CFTR | chr7-117144344 | c.C91T | p.R31C | C-T | Mother | |
| FEVR-131 | LRP5 | chr11-68174186 | c.G1996A | p.D666N | G-A | Father |
| CFTR | chr7-117251700 | c.G3205A | p.G1069R | G-A | Father | |
| FEVR-234 | LRP5 | chr11-68197061 | c.G3656A | p.R1219H | G-A | Father |
| KIF11 | chr10-94396989 | c.C1924G | p.P642A | C-G | Father |
One child (5.56%), subject FEVR-051, carried mutations in KIF11, LRP5, and CAPN5 at the same time, all inherited from both parents (Table 6).
Table 6.
Chongqing probands carrying 3 mutations including LRP5.
| Mutated gene | Mutation site | Nucleotide changes | Amino acid changes | Variation | Source | |
|---|---|---|---|---|---|---|
| FEVR-051 | LRP5 | chr11-68171037 | c.C1671A | p.F557L | C-A | Father |
| KIF11 | chr10-94396989 | c.C1924G | p.P642A | C-G | Mother | |
| CAPN5 | chr11-76830152 | c.G1244A | p.R415Q | G-A | Mother |
3.1.2. LRP5 mutations in Urumqi
Among the 3 LRP5-mutated probands in Urumqi, 5 mutation sites were identified. One child carried 3 different mutations (Table 7) Among the 3 LRP5-mutated probands, 0 subjects carried paternal mutations, 2 (66.67%) carried maternal mutations, 1 (33.33%) carried parental mutations (both parents had LRP5 mutations, and proband inherited the 1 variant from the mother and 2 variants from the father) (Tables 3 and 8).
Table 7.
LRP5 mutations sites in Urumqi probands.
| Mutation sites | Nucleotide changes | Amino acid changes | Variation | Subject no. |
|---|---|---|---|---|
| chr11-68153817 | c.1049C>T | p.R741G | C-T | FEVR-73963 |
| chr11-68192694 | c.1618A>G, c.3361A>G | p.N540D, p.N1121D | A-G | |
| chr11-68201253 | c.2204G>A, c.3947G>A | p.R735H, p.R1316H | G-A | |
| chr11-68153886 | c.1118G>T | p.R373L | G-T | FEVR-73921 |
| chr11-68154116 | c.1348C>T | p.R450C | C-T | FEVR-73931 |
Table 8.
Urumqi probands carrying 2 mutations including LRP5.
| Mutated gene | Mutation site | Nucleotide changes | Amino acid changes | Variation | Source | |
|---|---|---|---|---|---|---|
| FEVR-73963 | LRP5 | chr11-68153817 | c.1049C>T | p.T350M | C-T | Father |
| chr11-68192694 | c.1618A>G, c.3361A>G | p.N540D, p.N1121D | A-G | Father | ||
| chr11-68201253 | c.2204G>, c.3947G>A | p.R735H, p.R1316H | G-A | Mother | ||
| CFTR | Chr7-117246728 | c.2909G > A | p.G970D | G-A | Father |
3.2. LRP5 mutation-related phenotype analysis
Among 18 infants with LRP5 mutations, 16 (88.89%) were term infants and 2 (11.11%) were premature infants. Four (22.22%) had monocular disease and 14 (77.78%) had binocular disease. In terms of FEVR staging, among the 32 involved eyes of the 18 infants, 3 eyes were diagnosed with FEVR stage 1A (9.38%), 24 with stage 1B (75%), 2 with stage 2A (6.25%), and 3 with stage 2B (9.38%). None of the cases were identified as stages 3–5 (Table 9). Among these patients, stage 2B probands carried pathogenic genes synergistically with LRP5. In terms of lesion localization, 11 eyes (34.38%) had lesions in zone II and 21 (65.62%) had lesions in zone III. In terms of clinical signs, 2 eyes (6.25%) experienced retinal hemorrhage, 1 eye (3.13%) experienced opacity, and 1 eye experienced morning glory syndrome/staphyloma (3.13%).
Table 9.
Stages of diseased eyes in patients carrying LRP5 mutations.
| Stage | 1A | 1B | 2A | 2B |
|---|---|---|---|---|
| Eye | 3 | 24 | 2 | 3 |
| Ratio | 9.38% | 75% | 6.25% | 9.38% |
4. Discussion
The reported number of FEVR patients has increased as neonatal eye disease screening has normalized. With cumulative knowledge of FEVR, Chinese scholars have found that gaps exist among regions in terms of FEVR detection rates. A multicenter study has found that across regions in China, the FEVR detection rate among term infants was 1.19% and 0.36% among premature infants.[10] Our preliminary study found that in Chongqing, the FEVR detection rates among term infants were 0.92% and 0.68%, for premature infants.[11] The detection rates in different regions may vary. However, the popularization of gene sequencing technologies has increased the efficiency and accessibility of FEVR diagnosis. This study compared LRP5 mutation rates among FEVR patients from Chongqing and Urumqi and found a significant difference in mutation rates. However, the difference was not statistically significant, suggesting no potential correlations between mutation rates and geography, ethnicity, or sex. Among the LRP5-mutated probands investigated, the probands from Chongqing predominately inherited their mutations from their fathers (50%) and the probands from Urumqi predominately inherited their mutations from their mothers (66.67%). However, this numerical difference should not be attributed to geographical factors due to the limited sample size of Urumqi. A study outside of China found that among FEVR patients, LRP5 and FZD4 mutations were the most frequent, accounting for 19% and 15% of all mutations, respectively. NDP and TSPN12 were less frequent, accounting for 7% and 6%. ZNF408 mutations are the least frequent.[12] In this study, the LRP5 mutation frequencies in Chongqing and Urumqi were 20% and 18.75%, respectively, which are close to the accounts of studies outside of China. This added to the fact that the LRP5 detection rates were not significantly different.
In this study, no stage 3–5 phenotypes were found among LRP5-mutated patients, and all 2B probands carried pathogenic genes synergistic with LRP5. It is known that FEVRs become progressively more severe from stages 1 to 5. Studies have found that the NDP gene is associated with the most severe conditions, followed by FZD4 and TSPAN12, and LRP5 and ZNF408, which are associated with the least severe conditions.[13] In this study, the phenotypes of lens opacity and retinal hemorrhage were found to be related to the synergistic effects of LRP5 and CFTR and LRP5 and ZNF408 gene mutations, respectively. However, other LRP5 mutations were associated with less severe phenotypes. Thus, the presence of multiple mutations, in addition to LRP5 mutations, is more likely to translate into more severe phenotypes than LRP5 mutations alone. LRP5 mutations can lead to the development of type 4 FEVRs. Over 30 mutation sites have been shown to correlate with FEVRs.[14] In this study, 2 pairs of patients carried identical mutations: Patients FEVR-167 and FEVR-183 reported the same phenotype and were both diagnosed with stage 1B. However, FEVR-052 and FEVR-222 patients reported different phenotypes and were diagnosed at stage 1A in zone III and stage 1B in zone III. Thus, it was suggested that there is a possible correlation between FEVR phenotypes and mutated genes. However, no clear correlations between FEVR phenotypes and specific mutation sites were found in this study.
The correlation between FEVR phenotypes and mutation sites requires further investigation. Additionally, a recent study[15] identified 6 nonsynonymous DNA variants in the coding regions of the retina of premature babies in the FZD4 gene (p.H69Y, p.R127H, and p.Y.Y211H) or the LRP5 gene (p.R1219H, p.H1383P, and p.T.T1540M). At least 2 of these changes are predicted to be pathogenic. No similar changes were identified in TSPAN12 and NDP. Although there is insufficient evidence to corroborate the correlations between these changes and retinopathies, this study was ignored in this present study. This study provides a new direction for future research.
Acknowledgments
We are thankful for the patients who participated in this study.
Author contributions
Data curation: Chao Cen.
Formal analysis: Chao Cen.
Writing—original draft: Chao Cen, Liying He.
Writing—review & editing: Chao Cen, Liying He.
Funding acquisition: Liying He.
Project administration: Liying He.
Conceptualization: Ke Hu.
Validation: Ke Hu.
Abbreviations:
- FEVR
- familial exudative vitreoretinopathy
- SNV
- single nucleotide variants.
Supported by Innovation Project for Social Undertakings and Livelihood Security in Chongqing (CSTC2017shms-zdfX0049).
Institutional review board approval for the study was obtained from Ethics Committee of Women and Children’s Hospital of Chongqing Medical University. Ethical aspects of the studies and procedures related to clinical examination, human sample collection, and genetic analysis were approved by the Medical Ethics Committee of the Chongqing Health Center for Women and Children and Urumqi Health Center for Women and Children. All methods were performed in accordance with the relevant guidelines and regulations of the Declaration of Helsinki. Ethical Review number: (2018) No. 012.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
How to cite this article: Cen C, He L, Hu K, Tao X, Liu Y, Li Q, Zhou W. An analysis of LRP5 gene frequencies in infants with familial exudative vitreoretinopathy in Chongqing and Urumqi. Medicine 2025;104:30(e42702).
CC and HL contributed to this article equally.
Contributor Information
Chao Cen, Email: 190260112@qq.com.
Liying He, Email: fyyk2008@163.com.
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