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Wolfgang Berger, Detlev Boehm, Saskia Biskup, Susanne Kohl, Simone Schimpf-Linzenbold, Bernd Wissinger, John Neidhardt; Next Generation Genetic Testing And Candidate Gene Analysis In Retinal Diseases. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1829.
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Familial retinal degenerations and dysfunctions are characterized by a tremendous genetic heterogeneity and clinical variability of symptoms. More than 20 different clinical diagnoses involve mutations in more than 170 genes. Some of them are accompanied by extraocular clinical manifestations (syndromic forms), including for example deafness, mental retardation or renal abnormalities. Since few years, a variety of promising therapeutic strategies for these so far untreatable diseases are being developed. Genetic heterogeneity and clinical variability require efficient and reliable diagnostic tests in order to apply specific treatment. So far, high throughput genetic testing is not available for patients with these diseases.
Based on target enrichment coupled with next generation sequencing, we have established an efficient strategy to screen for mutations in 168 known retinal disease genes as well as more than 3.500 candidate genes.
Two genomic DNAs with 31 known sequence alterations in ABCA4, PRPH2, and ROM1 have been used as positive controls to evaluate the reliability of the technique. We confirmed more than 90% of the previously detected variants including missense and nonsense mutations as well as a single base pair insertion. Coverage of the corresponding genomic positions showed high variability. In addition, 18 patient samples were analyzed for causative mutations and several potentially pathogenic sequence alterations were detected.
This strategy will lead to the identification of disease-causing mutations in known genes but also in novel genes, which will unravel new biological processes underlying these diseases. Moreover, this approach will enable us to detect possible disease-modifying sequence variations.
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