Transcriptional Profiling of Patients With Fuchs Endothelial Corneal Dystrophy With and Without Trinucleotide Repeat Expansion in TCF4

Purpose: To investigate transcriptomic differences between patients with Fuchs endothelial corneal dystrophy (FECD) with and without trinucleotide repeat (TNR) expansion in the transcription factor 4 gene, as the genetic basis for patients with FECD lacking TNR expansion remains unclear. Methods: Bulk RNA sequencing was performed on corneal endothelial cells from 17 subjects: 10 patients with FECD [4 with repeat expansion lengths <50 (RE−) and 6 with expansions of 50 or more (RE+)] and 7 controls. Differential gene expression analysis was conducted using DESeq2. Principal component analysis (PCA), correlation matrix analysis, and heatmap visualization were used to evaluate gene expression patterns. Gene Ontology enrichment analysis was performed on differentially expressed genes (DEGs). Results: Analysis identified 509 DEGs (281 upregulated, 228 downregulated) between RE− and controls, and 640 DEGs (292 upregulated, 348 downregulated) between RE+ and controls. PCA revealed distinct gene expression patterns in both RE− and RE+ groups compared with controls. Between RE− and RE+ groups, only 10 DEGs were identified: ALDH3A1, ENSG00000286252, RNU6-645P, SNORD113-7, RNU6-429P, SNORA16A, COCH, EGFL6, SEMA3E, and ENSG00000228463. PCA, correlation matrix analysis, and heatmap visualization demonstrated high similarity in overall gene expression patterns between RE− and RE+ groups. Conclusions: Contrary to expectations, gene expression profiles showed remarkable similarity between patients with FECD with and without TNR expansion. Further investigation of the identified DEGs may provide insights into the role of TNR expansion in FECD pathophysiology.