Curation and bioinformatic analysis of strabismus genes supports functional heterogeneity and proposes candidate genes with connections to RASopathies

Gene. 2019 May 20;697:213-226. doi: 10.1016/j.gene.2019.02.020. Epub 2019 Feb 15.

Abstract

Strabismus refers to the misalignment of the eyes and occurs in 2-4% of individuals. The low-resolution label "strabismus" covers a range of heterogeneous defects, which makes it challenging to unravel this condition. Consequently a coherent understanding of the causes is lacking. Here, we attempt to gain a better understanding of the underlying genetics by combining gene curation, diverse bioinformatic analyses (including gene ontology, pathway mapping, expression and network-based methods) and literature review. Through a phenotype-based curation process, we identify high-confidence and permissive sets of 54 and 233 genes potentially involved in strabismus. These genes can be grouped into 10 modules that together span a heterogeneous set of biological and molecular functions, and can be linked to clinical sub-phenotypes. Multiple lines of evidence associate retina and cerebellum biology with the strabismus genes. We further highlight a potential role of the Ras-MAPK pathway. Independently, sets of 11 genes and 15 loci tied to strabismus with definitive genetic basis have been compiled from the literature. We identify strabismus candidate genes for 5 of the 15 reported loci (CHD7; SLC9A6; COL18A1, COL6A2; FRY, BRCA2, SPG20; PARK2). Finally, we synthesize a Strabismus Candidate Gene Collection, which together with our curated gene sets will serve as a resource for future research. The results of this informatics study support the heterogeneity and complexity of strabismus and point to specific biological pathways and brain regions for future focus.

Keywords: Bioinformatics; Gene curation; Gene set analysis; Genotype-to-phenotype; Strabismus.

MeSH terms

  • Computational Biology / methods
  • Data Curation / methods
  • Gene Ontology
  • Gene Regulatory Networks / genetics
  • Genes, ras / genetics
  • Humans
  • MAP Kinase Signaling System / genetics
  • Signal Transduction / genetics
  • Strabismus / genetics*
  • Strabismus / physiopathology
  • Transcriptome / genetics
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / physiology

Substances

  • Ubiquitin-Protein Ligases
  • parkin protein