Targeted next-generation sequencing analysis identifies novel mutations in families with severe familial exudative vitreoretinopathy

Mol Vis. 2017 Aug 23;23:605-613. eCollection 2017.


Purpose: Familial exudative vitreoretinopathy (FEVR) is a genetically and clinically heterogeneous disease, characterized by failure of vascular development of the peripheral retina. The symptoms of FEVR vary widely among patients in the same family, and even between the two eyes of a given patient. This study was designed to identify the genetic defect in a patient cohort of ten Chinese families with a definitive diagnosis of FEVR.

Methods: To identify the causative gene, next-generation sequencing (NGS)-based target capture sequencing was performed. Segregation analysis of the candidate variant was performed in additional family members by using Sanger sequencing and quantitative real-time PCR (QPCR).

Results: Of the cohort of ten FEVR families, six pathogenic variants were identified, including four novel and two known heterozygous mutations. Of the variants identified, four were missense variants, and two were novel heterozygous deletion mutations [LRP5, c.4053 DelC (p.Ile1351IlefsX88); TSPAN12, EX8Del]. The two novel heterozygous deletion mutations were not observed in the control subjects and could give rise to a relatively severe FEVR phenotype, which could be explained by the protein function prediction.

Conclusions: We identified two novel heterozygous deletion mutations [LRP5, c.4053 DelC (p.Ile1351IlefsX88); TSPAN12, EX8Del] using targeted NGS as a causative mutation for FEVR. These genetic deletion variations exhibit a severe form of FEVR, with tractional retinal detachments compared with other known point mutations. The data further enrich the mutation spectrum of FEVR and enhance our understanding of genotype-phenotype correlations to provide useful information for disease diagnosis, prognosis, and effective genetic counseling.

MeSH terms

  • Adolescent
  • Adult
  • Asian Continental Ancestry Group / genetics*
  • China / epidemiology
  • Cohort Studies
  • DNA Mutational Analysis
  • Eye Diseases, Hereditary
  • Familial Exudative Vitreoretinopathies
  • Female
  • Genetic Association Studies
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Low Density Lipoprotein Receptor-Related Protein-5 / genetics*
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Pedigree
  • Phenotype
  • Real-Time Polymerase Chain Reaction
  • Retinal Diseases / genetics*
  • Sequence Deletion*
  • Tetraspanins / genetics*
  • Young Adult


  • LRP5 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-5
  • TSPAN12 protein, human
  • Tetraspanins

Supplementary concepts

  • Familial Exudative Vitreoretinopathy