Genetic screen of African Americans with Fuchs endothelial corneal dystrophy

Abstract

Purpose: Fuchs endothelial corneal dystrophy (FECD) is a genetically heterogeneous disorder that has been primarily studied in patients of European or Asian ancestry. Given the sparse literature on African Americans with FECD, we sought to characterize the genetic variation in three known FECD candidate genes in African American patients with FECD.

Methods: Over an 8-year period, we enrolled 47 African American probands with FECD. All participants were clinically examined with slit-lamp biomicroscopy, and when corneal tissue specimens were available, histopathologic confirmation of the clinical diagnosis was obtained. The coding regions of known FECD susceptibility genes collagen, type VIII, alpha 2 (COL8A2); solute carrier family 4, sodium borate transporter, member 11 (SLC4A11); and zinc finger E-box binding homeobox 1 (ZEB1 [also known as TCF8]) were Sanger sequenced in the 47 probands using DNA isolated from blood samples.

Results: Twenty-two coding variants were detected across the COL8A2, SLC4A11, and ZEB1 genes; six were nonsynonymous variants. Three novel coding variants were detected: a synonymous variant each in COL8A2 and SLC4A11 and one nonsynonymous variant in ZEB1 (p.P559S), which is predicted to be benign and tolerated, thus making its physiologic consequence uncertain.

Conclusions: Variation in the COL8A2, SLC4A11, and ZEB1 genes is present in only a small fraction of our African American cases and as such does not appear to significantly contribute to the genetic risk of FECD in African Americans. This observation is on par with findings from previous sequencing studies involving European or Asian ancestry patients with FECD.

Figure 1

Variants in the collagen, type VIII, alpha 2 (COL8A2) gene on chromosome 1p34.3 that have been detected in patients with Fuchs endothelial corneal dystrophy (FECD). Solid cylinders represent coding portions of the gene, while light gray cylinders represent untranslated regions. The lines connecting each cylinder indicate splicing events, and the start and stop codons of the gene are indicated with bold font. The gene is drawn from 3′ to 5′ reflecting its physical orientation on the reverse strand of the reference genome. All variants in this figure are taken from previous FECD reports in the literature (black font) or are coding variants detected in African Americans with FECD in this report (red font). Variants are indicated with double-headed arrows: black arrows indicate coding-nonsynonymous variants (produce an amino acid change), while white arrows indicate coding-synonymous variants (do not produce an amino acid change). Variants marked with an asterisk (*) are newly identified variants in African Americans with FECD that have not been previously reported in patients with FECD.

Figure 2

Variants in the solute carrier family 4, sodium borate transporter, member 11 (SLC4A11) gene on chromosome 20p13 that have been detected in patients with Fuchs endothelial corneal dystrophy (FECD). The gene is drawn from 3′ to 5′ reflecting its physical orientation on the reverse strand of the reference genome. Figure drawn as described in the caption for Figure 1, with the red font indicating variants identified in our African American FECD cases and variants marked with an asterisk (*) indicating newly identified variants in African Americans with FECD that have not been previously reported in patients with FECD.

Figure 3

Variants in the zinc finger E-box binding homeobox 1 (ZEB1, also known as TCF8) gene on chromosome 10p11.22 that have been detected in patients with Fuchs endothelial corneal dystrophy (FECD). The gene is drawn from 5′ to 3′ reflecting its physical orientation on the forward strand of the reference genome. Drawn as described in the caption for Figure 1, with the red font indicating variants identified in our African American FECD cases and variants marked with an asterisk (*) indicating newly identified variants in African Americans with FECD that have not been previously reported in patients with FECD.