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Natalie A. Afshari, Mollie A. Minear, Jacqueline Rimmler, Elmer Balajonda, Shera Watson, Michael A. Hauser, R R. Allingham, Gordon K. Klintworth, Yi-Ju Li, Simon G. Gregory; Genetic screen of African-Americans with Fuchs endothelial corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5987.
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© ARVO (1962-2015); The Authors (2016-present)
To determine whether African-Americans (AAs) with Fuchs endothelial corneal dystrophy (FECD) have genetic variants in the COL8A2, SLC4A11, and ZEB1 (TCF8) genes.
African-Americans (AAs) with FECD were examined using slit-lamp biomicroscopy, corneal tissues obtained at corneal transplant were examined when available, and blood samples were obtained for DNA analysis. Primers covering coding portions of the three genes were either taken from the literature or designed with ExonPrimer and Primer3. Sequences were generated on one strand, and possible variants were confirmed on the opposite strand. All sequencing was generated either using BigDye Terminator chemistry and run on an ABI 3730 DNA Analyzer (both from Applied Biosystems), or was sent to Eton Biosciences, Inc. Sequences were examined with Sequencher 5.0 (Gene Codes Corporation). PolyPhen and SIFT were used to predict the severity of amino acid substitution for novel nonsynonymous variants, which were then screened in 753 AAs recruited as controls for a study of primary open-angle glaucoma (POAG) to determine frequency in non-FECD AAs.
70 subjects were enrolled, representing 40 unique families. We sequenced one case per family: 31 singletons and 9 multiplex family probands. In each gene, we detected several polymorphic SNPs previously reported in the HapMap and 1000 Genomes Project samples that are in dbSNP. Of previously reported variants in FECD patients, we detected p.R155Q in COL8A2; and p.A135A, p.R161R, p.S213S, p.N553N, and p.T833T in SLC4A11 in our subjects. We did not replicate any previously reported FECD coding variants in ZEB1. We detected five novel coding variants: p.A441A and p.Y648Y (COL8A2, each in one case); p.H728H and p.L841L (SLC4A11, each in 2 cases); and p.P559S (ZEB1, in one case). PolyPhen and SIFT predicted p.P559S to be benign and tolerated. One POAG control had p.P559S but was never specifically examined for FECD and is now lost to follow-up.
This is the first study to examine AAs with FECD for mutations in the three putative FECD genes. We detect both novel and previously reported variants in these genes at low frequencies, similar to what has been observed in previous reports. This suggests that AAs may have the same underlying genetic susceptibility to FECD as European-Americans and Asians.
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