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N.A. Afshari, Y.–J. Li, S. Gregory, M. Pericak–Vance, G.K. Klintworth; Genome Wide Linkage Scan in Fuchs Endothelial Corneal Dystrophy . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5902.
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© ARVO (1962-2015); The Authors (2016-present)
To establish the genetic basis of Fuchs corneal dystrophy (FCD) through a genome wide screen with single nucleotide polymorphism (SNP) linkage panel.
We performed slit lamp biomicroscopy on 92 affected or unaffected individuals from 22 families with FCD. This included one large multigenerational family with 18 members and 21 small multiplex families. A diagnosis of FCD was assigned if the individual had a prior corneal transplant with a histopathologic diagnosis of FCD or if the individual had severe corneal guttae and at least one family member who had undergone a corneal transplant with a histopathologic diagnosis of FCD. We genotyped FCD diagnosed individuals for the two reported FCD mutations in COL8A2 (L450W and Q455K). A genome wide linkage scan was performed using Illumina SNP linkage panel IV (5759 SNPs). Parametric two–point linkage analyses (both recessive and dominant models ) were calculated using FASTLINK/HOMOG. Nonparametric multipoint linkage analyses using Allegro were generated on chromosomes with consistently high two point LOD scores (LOD > 1.5)
We did not identify the two reported mutations in COL8A2 within any of the 92 samples. Genome–wide analysis identified five regions with consistent linkage signals from all analyses in chromosomes 1, 7, 15, 17, and X. The highest two point LOD scores were found on chromosome 15q for the total data set. The LOD score was 3.26 for the recessive model and 2.48 for the dominant model. Multipoint linkage analysis also identified a linkage peak on chromosome 15q with a LOD>2. Some linkage regions were identified on chromosomes 7 and X using the total dataset. Analysis of the 21 families indicated that the findings on chromosome 7, 15, X are derived from the small family aggregates, supporting a complex genetic cause in this subset of families. Chromosome 17q showed LOD>2 by both two point and multipoint analyses in the overall dataset, with the bulk of linkage information coming from the large multigenerational family. A region in chromosome 1p close to the previously identified COL8A2gene in two families with FCD was found to have a two point LOD >2.
We have recruited a significant number of individuals in families with FCD and through whole genome SNP analysis have identified potential linkage regions on chromosomes 1, 7, 15, 17, and X warranting validation in a second FCD dataset.
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