Novel mutation in TSPAN12 leads to autosomal recessive inheritance of congenital vitreoretinal disease with intra-familial phenotypic variability

Am J Med Genet A. 2014 Dec;164A(12):2996-3002. doi: 10.1002/ajmg.a.36739. Epub 2014 Sep 22.


Developmental malformations of the vitreoretinal vasculature are a heterogeneous group of conditions with various modes of inheritance, and include familial exudative vitreoretinopathy (FEVR), persistent fetal vasculature (PFV), and Norrie disease. We investigated a large consanguineous kindred with multiple affected individuals exhibiting variable phenotypes of abnormal vitreoretinal vasculature, consistent with the three above-mentioned conditions and compatible with autosomal recessive inheritance. Exome sequencing identified a novel c.542G > T (p.C181F) apparently mutation in the TSPAN12 gene that segregated with the ocular disease in the family. The TSPAN12 gene was previously reported to cause dominant and recessive FEVR, but has not yet been associated with other vitreoretinal manifestations. The intra-familial clinical variability caused by a single mutation in the TSPAN12 gene underscores the complicated phenotype-genotype correlation of mutations in this gene, and suggests that there are additional genetic and environmental factors involved in the complex process of ocular vascularization during embryonic development. Our study supports considering PFV, FEVR, and Norrie disease a spectrum of disorders, with clinical and genetic overlap, caused by mutations in distinct genes acting in the Norrin/β-catenin signaling pathway.

Keywords: Norrie disease; TSPAN12; familial exudative vitreoretinopathy (FEVR); persistent fetal vasculature (PFV); whole exome sequencing (WES).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Blindness / congenital*
  • Blindness / genetics
  • Computational Biology
  • Exome / genetics
  • Eye Diseases, Hereditary
  • Familial Exudative Vitreoretinopathies
  • Genes, Recessive
  • Genetic Diseases, X-Linked
  • Humans
  • Molecular Sequence Data
  • Nervous System Diseases / genetics*
  • Persistent Hyperplastic Primary Vitreous / genetics*
  • Phenotype*
  • Point Mutation / genetics*
  • Retinal Degeneration
  • Retinal Diseases / genetics
  • Sequence Analysis, DNA
  • Spasms, Infantile / genetics*
  • Tetraspanins / genetics*


  • TSPAN12 protein, human
  • Tetraspanins

Supplementary concepts

  • Norrie disease