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A. L. Vincent, D. M. Markie, B. De Karolyi, C. E. Wheeldon, C. N. Grupcheva, C. N. J. McGhee; Exclusion of Known Corneal Dystrophy Genes in an Autosomal Dominant Pedigree of a Variant Anterior Membrane Corneal Dystrophy With Recurrent Erosions and Large Flecks. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4314.
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The inherited corneal dystrophies represent a group of clinically and genetically heterogeneous disorders of the cornea, with many genes identified to date. With the advances in phenotyping tools, and availability of molecular characterisation, an increasing number of ‘atypical’ or variant dystrophies are being described. We aimed to determine the underlying causative genetic mechanism in a three generational pedigree affected with an autosomal dominant variant anterior membrane dystrophy with features intermediate between a fleck and granular phenotype, similar to the description of Grayson-Wilbrandt.
Twenty affected and unaffected members of a three generational family were examined, clinically characterised and DNA collected following informed consent. Mutational analysis of two corneal genes (TGFBI and TCF8) was undertaken, with subsequent testing with the Asper Corneal Dystrophy gene chip. Linkage to 11 known corneal gene loci (COL8A2, TACSTD2, PIP5K3, GSN, KERA, VSX1, COL6A1, MMP9, KRT3, 3p14-q13, and 15q22.33-24) was undertaken using polymorphic markers, and haplotypes constructed. Multipoint linkage analysis was performed to generate LOD scores and produce LOD plots across the candidate intervals.
No pathogenic sequence variations were detected in TGFBI and TCF8, nor on the Asper Corneal dystrophy gene chip (302 mutations in 12 genes). Multipoint linkage analysis of 11 known corneal genes and loci generated negative LOD plots and was able to exclude all genes tested
Exclusion of linkage to candidate corneal genes and loci, combined with an absence of pathogenic mutations in known corneal genes in this autosomal dominant pedigree, suggest a different genetic causative mechanism in this dystrophy than the previously documented corneal genes. This variant phenotype of an anterior membrane dystrophy with recurrent corneal erosions and flecks may therefore provide an opportunity to identify a new gene responsible for corneal disease.
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