Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease

Ophthalmology. 2017 Sep;124(9):1314-1331. doi: 10.1016/j.ophtha.2017.04.008. Epub 2017 May 27.


Purpose: To devise a comprehensive multiplatform genetic testing strategy for inherited retinal disease and to describe its performance in 1000 consecutive families seen by a single clinician.

Design: Retrospective series.

Participants: One thousand consecutive families seen by a single clinician.

Methods: The clinical records of all patients seen by a single retina specialist between January 2010 and June 2016 were reviewed, and all patients who met the clinical criteria for a diagnosis of inherited retinal disease were included in the study. Each patient was assigned to 1 of 62 diagnostic categories, and this clinical diagnosis was used to define the scope and order of the molecular investigations that were performed. The number of nucleotides evaluated in a given subject ranged from 2 to nearly 900 000.

Main outcome measures: Sensitivity and false genotype rate.

Results: Disease-causing genotypes were identified in 760 families (76%). These genotypes were distributed across 104 different genes. More than 75% of these 104 genes have coding sequences small enough to be packaged efficiently into an adeno-associated virus. Mutations in ABCA4 were the most common cause of disease in this cohort (173 families), whereas mutations in 80 genes caused disease in 5 or fewer families (i.e., 0.5% or less). Disease-causing genotypes were identified in 576 of the families without next-generation sequencing (NGS). This included 23 families with mutations in the repetitive region of RPGR exon 15 that would have been missed by NGS. Whole-exome sequencing of the remaining 424 families revealed mutations in an additional 182 families, and whole-genome sequencing of 4 of the remaining 242 families revealed 2 additional genotypes that were invisible by the other methods. Performing the testing in a clinically focused tiered fashion would be 6.1% more sensitive and 17.7% less expensive and would have a significantly lower average false genotype rate than using whole-exome sequencing to assess more than 300 genes in all patients (7.1% vs. 128%; P < 0.001).

Conclusions: Genetic testing for inherited retinal disease is now more than 75% sensitive. A clinically directed tiered testing strategy can increase sensitivity and improve statistical significance without increasing cost.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Exome / genetics
  • Eye Diseases, Hereditary / genetics*
  • Eye Proteins / genetics*
  • Family Health
  • Female
  • Genetic Testing
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Mutation*
  • Pedigree
  • Retinal Diseases / genetics*
  • Retrospective Studies
  • Sensitivity and Specificity
  • Sequence Analysis, DNA
  • United States


  • Eye Proteins