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K. Nikopoulos, C. Gilissen, A. Hoischen, C. E. van Nouhuys, F. N. Boonstra, H. Scheffer, L. H. Hoefsloot, J. A. Veltman, F. P. M. Cremers, R. W. J. Collin; Next-Generation Sequencing of a 40-Mb Region Reveals Tspan12 Mutations in Patients With Autosomal Dominant Familial Exudative Vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6349.
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To date, mutations in three genes (FZD4, LRP5 and NDP) have been shown to cause familial exudative vitreoretinopathy (FEVR). The purpose of this study was to determine the genetic defect in 11 families with autosomal dominant FEVR that do not carry mutations in the known FEVR genes.
Individuals from two large Dutch pedigrees were genotyped using genome-wide SNP arrays, revealing a novel locus for FEVR. Targeted array-based sequence capture combined with next-generation sequencing was applied in the proband of one family, by analyzing all exons and intron-exon boundaries of 338 genes, together with all microRNAs and highly conserved genomic regions in this novel locus.
Genome-wide SNP analysis in two FEVR families identified a novel 40-Mb FEVR locus on chromosome 7, and subsequent microsatellite marker analysis suggested similar at risk haplotypes in patients of both families. Next-generation sequencing detected the p.A237P variant in the transmembrane 4 superfamily member 12 protein, encoded by TSPAN12. Sanger sequencing of 10 additional unrelated FEVR families identified the same missense mutation in 4 of them, together with one additional mutation (p.G188R) in one other family.
We have identified TSPAN12 as a novel causative gene for adFEVR, being only the third autosomal gene described for this disease and mutated in five out of eleven Dutch families without FZD4 and LRP5 mutations. The protein has very recently been implicated in regulating the development of retinal vasculature, together with FZD4, LRP5 and NDP. Moreover, we have proven as one of the first groups ever, the enormous potential of next generation sequencing technology combined with array-based sequence capture, by identifying a single causative base-pair substitution within a 40-Mb region containing more than 300 genes.
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