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Zhongqi Ge, Eric Zaneveld, Vincent Sun, Hui Wang, Richard G Weleber, Mark E Pennesi, Robert K Koenekoop, Ruifang Sui, Rui Chen; Panel-based Next Generation Sequencing improves mutation detection in Cone Rod Dystrophy patients. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2870.
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© ARVO (1962-2015); The Authors (2016-present)
Previous molecular diagnostic studies of Cone Rod Dystrophy had a rate of solution below 25%. In this study, we aim to carry out a comprehensive molecular diagnosis of a large CRD cohort by testing both known CRD genes and other retinal disease genes to increase our diagnostic accuracy and reveal new genotype-phenotype associations.
146 sporadic Cone Rod Dystrophy (CRD) and Cone Dystrophy (CD) patients were recruited from various ethnicities including Caucasian, Han Chinese, and African American. A custom retinal panel including all known CRD and CD genes was used for Next Generation Sequencing based genetic testing of these patients. Mutations identified were further Sanger validated and subjected to segregation tests when parent DNA was available.
Causative mutations in known CRD genes were found in 49 cases (33.6%), including 2 cases where mutations were found in syndromic CRD genes CNNM4 and ALMS1. Consistent with previous studies, ABCA4 and RPGR were the most frequently mutated genes found in this cohort and accounted for 15 and 5 solved cases, respectively. Interestingly, we found genes that showed ethnic specificity. For example, mutations in PRPH2 and CNGA3 were only identified in Caucasians, while PROM1 mutations were exclusively found in Chinese patients. In addition, mutations in other nonsyndromic and syndromic retinal disease genes such as Retinitis Pigmentosa, Macular Dystrophy, and Bardet-Biedl syndrome were found in another 17 cases (11.6%). For example, CRB1 mutations, previously shown to cause Leber Congenital Amaurosis, were found in 4 patients. These findings may refine clinical diagnosis for some patients or implicate that new genes can cause CRD phenotype.
This is the first comprehensive NGS based molecular diagnosis of CRD patients from multiple ethnicities involved. Our study demonstrated that panel-based NGS method is efficient, economic and sufficiently precise for molecular diagnosis CRD. Novel mutations identified will enrich our understanding of the genetic variations of CRD genes and lead to better molecular diagnosis of this disease.<br /> <br /> Acknowledgement: We would like to thank the patients the Research Group for their valuable contribution to this research. eyeGENE samples were obtained from the National Institutes of Health/National Eye Institute - eyeGENE(r) - Protocol 06-EI-0236.
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