Genotype-phenotype associations in familial exudative vitreoretinopathy: A systematic review and meta-analysis on more than 3200 individuals

PLoS One. 2022 Jul 13;17(7):e0271326. doi: 10.1371/journal.pone.0271326. eCollection 2022.


Objective: To systematically review the relationship between genotypes and clinical phenotypes of Familial exudative vitreoretinopathy (FEVR) to support risk estimation and therapeutic decisions.

Design: Systematic review with meta-analysis.

Data sources: The data of our study were collected from PubMed, Embase, Web of Science, Cochrane, CBM, China National Knowledge Infrastructure (CNKI), WAN FANG and VIP databases since inception to August 2021.

Results: A total of 3257 patients from 32 studies were included according to the inclusion and exclusion criteria. Among all the cases, the mutation frequencies of LRP5, FZD4, NDP, TSPAN12, ZNF408 and KIF11 were 13.6%, 11.5%, 4.6%, 6.7%, 1.6%, and 5.7%, respectively. We found that the patients with NDP and FZD4 suffer more severe symptoms, among which 86.4% patients of NDP and 78.6% patients of FZD4 were in the advanced stage of FEVR. Retinal detachment is the most frequent symptom with patients of LRP5 and NDP mutations, accounting for 51.9% and 64.5%, respectively. For the patients with the mutation of TSPAN12, retinal fold is the most common clinical manifestation, and suffer the mildest clinical phenotypes compared with the other three genes.

Conclusion: The results of the meta-analysis indicate that different types of genetic mutations occur at different frequencies. In addition, the clinical manifestations of FEVR are related to the type of gene mutation. Therefore, targeted treatment strategies and follow-up recommendations should be adopted for different pathogenic genes of FEVR.

Publication types

  • Meta-Analysis
  • Systematic Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics
  • Eye Diseases, Hereditary* / genetics
  • Familial Exudative Vitreoretinopathies
  • Frizzled Receptors / genetics
  • Genetic Association Studies
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-5 / genetics
  • Mutation
  • Pedigree
  • Retinal Diseases* / genetics
  • Tetraspanins / genetics
  • Transcription Factors / genetics


  • DNA-Binding Proteins
  • FZD4 protein, human
  • Frizzled Receptors
  • Low Density Lipoprotein Receptor-Related Protein-5
  • TSPAN12 protein, human
  • Tetraspanins
  • Transcription Factors
  • ZNF408 protein, human

Grants and funding

This project was supported by the Postdoctoral scientific research developmental fund of Heilongjiang Province (LBH-Q17106) and Scientific Research and Innovation Fund of the First Affiliated Hospital of Harbin Medical University (2017Y008). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the view of the foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.