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Cindy Wen, Jason Scott Salvo, Mingchu Xu, Hui Wang, Catherine Shi, Danni Lin, Michael Ai, Hongrong Luo, Rui Chen, Kang Zhang; Next-generation sequencing and novel variant determination in a cohort of 92 familial exudative vitreoretinopathy patients. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1243.
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© ARVO (1962-2015); The Authors (2016-present)
Familial exudative vitreoretinopathy (FEVR) is a genetic disorder that causes visual impairment and retinal detachment in children. To date, the contribution of mutations in the genes linked to the disease is not well documented due the limited number of studies for systematic molecular characterization of the patient cohorts. We performed a comprehensive molecular screen for all five genes associated with FEVR using next-generation sequencing (NGS) technology in a large cohort of 92 FEVR probands in order to investigate mutation spectrum in these patients, which will allow for a better understanding of the disease mechanism, molecular diagnosis and improved treatment of this debilitating condition.
Sequencing libraries from 92 FEVR patients were generated using a custom capture panel to enrich for 163 known or suspected retinal disease causing genes in humans. Samples were processed using next generation sequencing (NGS) techniques followed by data analysis to identify and classify single nucleotide variants and indels. Sanger validation and segregation testing were used to verify suspected variants.
Of the cohort of 92, 45 patients were potentially solved (48.9%). Specifically, mutations in low-density lipoprotein receptor-related protein 5 (LRP5), frizzled-4 (FZD4), tetraspanin-12 (TSPN12), Norrie disease protein (NDP), and zinc finger protein 408 (ZNF408) account for 19.6%, 15.2%, 8.7%, 6.5%, and 1.1% of patients respectively. In addition, 48 cases remain unsolved, representing 52% of our patient cohort. Out of the 48 alleles identified in this study, over 85% (41/48) are novel. 18 of the novel variants discovered were highly likely to cause FEVR due to the nature of these variants (frameshifting, indels, splicing mutations, and nonsense variants types).
We determined probable disease causing variants in a large number of FEVR patients, the majority of which were novel. This is a large study of FEVR utilizing NGS which will aid genetic diagnosis and therapeutic development of FEVR.
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