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Next generation sequencing (NGS) test for inherited retinal degenerations (IRDs) shows sensitivity and specificity of 97.9% and 100%, respectively

New research, published in the journal Genetics in Medicine, has shown that a panel-based genetic diagnostic test for inherited eye diseases is both highly accurate and reproducible. The test, referred to as “GEDi” (genetic eye disease), and offered under CLIA certification by the Ocular Genetics Institute (OGI) at the Massachusetts Eye and Ear Infirmary (MEEI), is designed to detect genes that are already known to cause disease. The test uses a target enrichment and NGS strategy employing 257 probes to target coding exons, 5′-/3′-untranslated regions (UTRs) and deep intronic regions known to harbor pathogenic mutations associated with the 214 known IRD disease genes described in the Retinal Information Network database ( [as of April 2013]). In addition, the probes also include 8 early-onset glaucoma and optic-atrophy genes, 24 candidate IRD disease genes, 9 age-related macular degeneration risk factor genes and 1 non-syndromic hearing loss gene. In total, the targeted regions comprise 1,210,190 base pairs (703,980-bp coding sequence).


The research group, based at Harvard Medical School, Boston, Massachusetts, performed rigorous analysis on the test to measure the sensitivity, specificity, and reproducibility, as well as clinical sensitivity. The test was shown to be highly reproducible and accurate, with sensitivity and specificity of 97.9% and 100%, respectively, for single-nucleotide variant detection. Importantly, the sensitivity for variant detection appeared superior to the 88.3% achieved by a whole-exome sequencing (WES) approach. A prospective testing of 192 patients with IRDs showed that the clinical sensitivity of GEDi is high, with a diagnostic rate of 51%. In comparing the GEDi approach with WES, the authors state that, “although WES is now available as a clinical diagnostic test at some centers and reports of using WES for diagnostic testing have been published, quantitation of the performance characteristics of the GEDi test makes identifying and quantifying the advantages of selective targeted enrichment over WES possible”. In addition to the advantages of selective enrichment over WES for diagnostic testing, the authors argue that the turnaround time for the GEDi “panel” test when run on a MiSeq NGS platform is approximately 24 hours, compared to WES samples run on a HiSeq 2000 instrument which take approximately12 days. In terms of costs, the GEDi testing per patient (as of August 2014) was ~$430, compared to $1,325 per patient for WES. What WES does offer over GEDi is the ability to detect new mutations and or new genetic involvements not previously known. The clinical sensitivity of the GEDi test was 51% which suggests that the other 49% of subjects with a negative GEDi result may harbor mutations in novel disease genes or in noncoding portions of known genes or have acquired a pathology arising from copy-number variations which are difficult to detect with sequence-based approaches.


In concluding their study the authors of the research stated that the GEDi “test offers a number of advantages as a clinical diagnostic test for patients with inherited eye disorders. Given the potential for gene-based therapies for inherited disorders in general and inherited eye disorders in particular, genetic diagnostic testing will increasingly be necessary for the optimal care of patients with genetic diseases. Furthermore, the GEDi test statistics make a strong case for the use of targeted tests in the clinical setting because they are highly accurate and reproducible, and have better overall performance than more general tests such as conventional WES analyses”.