Retinal Diseases Caused by Mutations in Genes Not Specifically Associated with the Clinical Diagnosis

PLoS One. 2016 Oct 27;11(10):e0165405. doi: 10.1371/journal.pone.0165405. eCollection 2016.


Purpose: When seeking a confirmed molecular diagnosis in the research setting, patients with one descriptive diagnosis of retinal disease could carry pathogenic variants in genes not specifically associated with that description. However, this event has not been evaluated systematically in clinical diagnostic laboratories that validate fully all target genes to minimize false negatives/positives.

Methods: We performed targeted next-generation sequencing analysis on 207 ocular disease-related genes for 42 patients whose DNA had been tested negative for disease-specific panels of genes known to be associated with retinitis pigmentosa, Leber congenital amaurosis, or exudative vitreoretinopathy.

Results: Pathogenic variants, including single nucleotide variations and copy number variations, were identified in 9 patients, including 6 with variants in syndromic retinal disease genes and 3 whose molecular diagnosis could not be distinguished easily from their submitted clinical diagnosis, accounting for 21% (9/42) of the unsolved cases.

Conclusion: Our study underscores the clinical and genetic heterogeneity of retinal disorders and provides valuable reference to estimate the fraction of clinical samples whose retinal disorders could be explained by genes not specifically associated with the corresponding clinical diagnosis. Our data suggest that sequencing a larger set of retinal disorder related genes can increase the molecular diagnostic yield, especially for clinically hard-to-distinguish cases.

MeSH terms

  • Adolescent
  • Adult
  • Child
  • DNA Copy Number Variations
  • DNA Mutational Analysis
  • Female
  • Gene Deletion
  • Heterozygote
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Mutation*
  • Retinal Diseases / diagnosis*
  • Retinal Diseases / genetics*

Grant support

This work is partially supported by “Research to Prevent Blindness, New York” to RAL. The funder provided support in the form of salaries for author RAL, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of this author are articulated in the ‘author contributions’ section.