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Suma P Shankar, Jiong Yan, Scott R Lambert, Amy K Hutchinson, Phoebe Lenhart, Vincent Thomas Ciavatta, Madhuri Hegde; Next-generation Sequencing Panel for Molecular Diagnosis in the Eye Clinic -Identification of Novel Mutations and the Saga of Variants of Unknown Significance. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6391.
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To evaluate the utility of Next Generation Sequencing panel for inherited eye diseases in a clinical setting. The genetic heterogeneity and phenotypic variability for many eye diseases has been well described. We hypothesized that given the genetic heterogeneity and the possibility of private, novel mutations, next generation panels would be an ideal method for clinical use.
We developed the Emory Next Generation Sequencing panel with 144 genes causing eye disorders such as retinitis pigmentosa ( both isolated and syndromic), achromatopsia, cone rod dystrophy, vitreoretinopathies, anterior segment dysgenesis and so on. A number of subpanel testing using the same NextGen Panel for more defined phenotypes such as for Leber congenital amaurosis was also available. Testing for comprehensive retinal panel was sent for 31 individuals and subpanels for 38 individuals. All individuals had detailed eye exams and an initial diagnosis of an inherited eye disorder.
We identified pathogenic/disease-causing variants in 22 individuals having the diagnosis of RP, achromatopsia, Stickler syndrome and Stargardt’s disease. Five individuals in whom testing was completed had variants of unknown significance. Testing is pending in 41 individuals.
Next generation sequencing panel is a useful means of achieving rapid test results and making a molecular diagnosis. When a definitive pathogenic mutation is identified, we are able to provide more accurate accurate diagnosis, prognosis, clinical trial or treatment options and genetic counseling regarding recurrence risks to families. In instances where a missense variant or a silent change that has not been previously reported as either a polymorphism or associate with disease is identified, further testing of family members or functional studies are required. Even among individuals with a definitive pathogenic mutation, when additional VOUS are identified, the possibility of modifying action of the VOUS has to be considered. As more data becomes available, patterns may begin to emerge for likely modifiers. Clinical testing laboratories have to continue posting the newly identified VOUS and mutations on data bases freely available to all and inform the physicians ordering tests of change in the status of a VOUS.
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