Whole-Exome Sequencing of Patients With Posterior Segment Uveitis

Am J Ophthalmol. 2021 Jan:221:246-259. doi: 10.1016/j.ajo.2020.07.021. Epub 2020 Jul 21.


Objective: To elucidate molecular risk factors for posterior segment uveitis using a functional genomics approach.

Design: Genetic association cohort study.

Methods: Setting: Single-center study at an academic referral center.

Study population: 164 patients with clinically diagnosed uveitis of the posterior segment.

Main outcome measures: Exome sequencing was used to detect variants identified in 164 patients with posterior segment uveitis. A phenotype-driven analysis, protein structural modeling, and in silico calculations were then used to rank and predict the functional consequences of key variants.

Results: A total of 203 single nucleotide variants, in 23 genes across 164 patients, were included in this study. Both known and novel variants were identified in genes previously implicated in specific types of syndromic uveitis-such as NOD2 (Blau syndrome) and CAPN5 NIV (neovascular inflammatory vitreoretinopathy)-as well as variants in genes not previously linked to posterior segment uveitis. Based on a ranked list and protein-protein-interaction network, missense variants in NOD-like receptor family genes (NOD2, NLRC4, NLRP3, and NLRP1), CAPN5, and TYK2 were characterized via structural modeling and in silico calculations to predict how specific variants might alter protein structure and function. The majority of analyzed variants were notably different from wild type.

Conclusions: This study implicates new pathways and immune signaling proteins that may be associated with posterior segment uveitis susceptibility. A larger cohort and functional studies will help validate the pathogenicity of the mutations identified. In specific cases, whole-exome sequencing can help diagnose nonsyndromic uveitis in patients harboring known variants for syndromic inflammatory diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Calpain / genetics*
  • Child
  • Child, Preschool
  • Exome Sequencing*
  • Female
  • Genetic Association Studies
  • Humans
  • Inflammasomes / metabolism
  • Male
  • Middle Aged
  • Mutation, Missense
  • NLR Proteins / genetics*
  • Proteomics
  • TYK2 Kinase / genetics*
  • Uveitis, Posterior / genetics*
  • Uveitis, Posterior / metabolism


  • Inflammasomes
  • NLR Proteins
  • TYK2 Kinase
  • TYK2 protein, human
  • Calpain
  • Capn5 protein, human