CTG18.1 Expansion is the Best Classifier of Late-Onset Fuchs' Corneal Dystrophy Among 10 Biomarkers in a Cohort From the European Part of Russia

Abstract

PURPOSE. To assess the occurrence and diagnostic performance of nine single-nucleotide variants (SNVs) in the TCF4, SLC4A11, LOXHD1, and AGBL1 genes and the CTG18.1 trinucleotide repeat expansion in a Russian cohort of Fuchs' endothelial corneal dystrophy (FECD) patients. METHODS. This retrospective case-control study included 100 patients diagnosed with FECD (cases) and 100 patients with cataracts (controls). Blood DNA was used to perform PCR and subsequent Sanger sequencing of rs613872 and rs17595731 in TCF4, c.99-100delTC, rs267607065, rs267607064, and rs267607066 in SLC4A11, rs113444922 in LOXHD1, and rs181958589 and rs185919705 in AGBL1. The number of CTG18.1 trinucleotide repeats was determined by a combination of conventional PCR or triplet primed PCR with fragment analysis. RESULTS. At least one rs613872 marker allele was found in 78% of FECD patients and 21% of controls, and at least one rs17595731 marker allele was found in 14% and 2%, respectively. CTG18.1 trinucleotide expansion (>40 repeats) was detected in 72% of FECD patients and 5% of controls. Marker alleles of the tested SNVs in SLC4A11, LOXHD1, and rs185919705 in AGBL1 were not found in our FECD cohort. One FECD patient carried the marker allele of the rs181958589 SNV. Analysis of the diagnostic performance of individual markers in TCF4 and their combinations showed that the CTG18.1 repeat expansion was the best classifier for FECD (AUC ¼ 0.84). CONCLUSIONS. Patients carrying CTG18.1 repeat expansion constituted a high proportion of the Russian FECD cohort; therefore, this marker is suitable for development of diagnostic and therapeutic approaches.

Lower Fractions of TCF4 Transcripts Spanning over the CTG18.1 Trinucleotide Repeat in Human Corneal Endothelium

“…Currently, association of the TCF4 repeat expansion ( n > 50) and FECD has been reported in several populations [ 7 , 8 , 9 , 10 , 11 ]. In other studies, association of FECD and (CTG) n repeat length over 40 has also been shown [ 12 , 13 , 14 , 15 ]. Functional analyses of the TCF4 RNA transcripts spanning over the expanded CTG18.1 have revealed that the repeat expansion tract folds into secondary structures termed RNA nuclear foci in corneal endothelial cells [ 16 , 17 , 18 ].…”

Dataset on transcriptome profiling of corneal endothelium from patients with Fuchs endothelial corneal dystrophy

“…Disease stage was identified according to the Volkov and Dronov classification as described in Ref. [1] .…”

“…Identification of the number of CTG repeats within the CTG18.1 allele in the TCF4 gene was carried out using short tandem repeat (STR) and triplet primed PCR (TP-PCR) techniques exactly according to the procedure described in Ref. [1] . The TCF4 allele was classified as expanded if the number of CTG repeats was ≥40 according to previously reported literature [2] , [3] .…”

DNA methylation changes and increased mRNA expression of coagulation proteins, Factor V and Thrombomodulin in Fuchs endothelial corneal dystrophy

“…Later, an even stronger association was found to a cytosine-thymine-guanine (CTG)n repeat expansion in an intron of TCF4, denoted as the CTG18.1 locus, 43 kb from the original SNP [8]. Today, multiple studies on the TCF4 repeat expansion and FECD have been conducted in several populations, all showing convincing association to FECD with repeat lengths over 40-50 [9][10][11][12][13][14][15][16][17]. Expansion of the CTG18.1 locus in the TCF4 gene makes FECD one of the most common tri-nucleotide repeat disorders along with myotonic dystrophy (DM), Huntington disease (HD), Spinocerebellar ataxia (SCA), Friedreich ataxia (FA) and Fragile X syndrome (FRAXA) [18].…”