FECD3_TCF4
- Gene
- TCF4
- Disease
- FECD3
- Inheritance
- AD
- Classification
- Definitive
- Total Score
- 18
- Publications Reviewed
- 8
- Publication Span
- 9.41 years
- Last Updated
- 08/18/2025
- Curator(s)
- Macayla Weiner, Laurel Hiatt, Elbay Aliyev
Description
Fuchs endothelial corneal dystrophy 3 (FECD3) is associated with an intronic TCF4 CTG/TGC trinucleotide repeat expansion (CTG18.1) with autosomal dominant inheritance and incomplete penetrance. Multiple independent cohorts show strong enrichment of expanded alleles in FECD cases versus controls, and family studies support segregation in a subset of kindreds. Functional studies in FECD corneal endothelial cells show repeat-associated CUG RNA foci, sequestration of MBNL splicing factors, altered mRNA splicing, and rescue of foci/splicing phenotypes after repeat-targeted ASO treatment.
Genetic evidence
Total: 12
| Singular Evidence | Probands | PMID:25168903 | 6 | Targeted sequencing of TCF4 in leukocyte DNA from 68 FECD subjects and 16 unaffected controls found TGC expansion >50 repeats in 46/68 affected subjects and 1/16 controls; no single variant perfectly segregated with disease. |
| Singular Evidence | Probands | PMID:24255041 | 6 | In 120 unrelated Caucasian FECD probands and 100 controls, expanded CTG18.1 (≥40 repeats) was significantly associated with FECD (OR 32.3, 95% CI 13.4–77.6). |
| Collective Evidence | Allele | PMID:25168903 | 1 | Reduced penetrance was noted: TGC expansion >50 repeats occurred in one unaffected control in this cohort, and the authors discuss unaffected older expansion carriers. |
| Collective Evidence | Segregation | PMID:24255041 | 1.5 | Expanded CTG18.1 cosegregated with FECD in 15/29 families with complete penetrance and 3/29 with incomplete penetrance; one representative family had maximum LOD 0.90. |
| Statistics | Case-control data | PMID:30267097 | 6 | Russian case-control cohort of 100 FECD cases and 100 cataract controls found CTG18.1 expansion >40 repeats in 72% of cases versus 5% of controls; CTG18.1 was the best classifier among tested markers (AUC 0.84). |
| Statistics | Case-control data | PMID:25168903 | 6 | In 68 FECD cases and 16 controls, TGC expansion >50 repeats was observed in 46/68 cases versus 1/16 controls; repeat expansion was a better predictor than other TCF4-region variants but was not perfectly concordant with disease. |
| Statistics | Case-control data | PMID:28832669 | 6 | Australian cohort of 189 advanced late-onset FECD cases and 183 controls showed association of expanded TGC repeat ≥40 repeats with FECD (P=2.58×10−22; OR=15.66, 95% CI 7.79–31.49), with expanded genotype in 51% of cases versus 5% of controls. |
| Statistics | Case-control data | PMID:27755191 | 6 | In 574 FECD participants, expanded allele carriers had higher transplantation frequency (78/357, 21.8%) than non-carriers (28/217, 12.9%; P=0.007) and higher age-adjusted transplantation likelihood (HR 1.64, 95% CI 1.05–2.55). |
8 rows
Experimental evidence
Total: 6
| Function | Biochemical function | PMID:25593321 | 0.5 | Expanded TCF4 CUG-repeat RNA foci in FECD corneal endothelial cells co-localized with and sequestered MBNL1, consistent with RNA-mediated toxicity. |
| Function | Protein interaction | |||
| Function | Regulatory impact | PMID:29526280 PMID:25593321 | 1 | pmid:25593321 showed CTG18.1 expansion-positive FECD corneal endothelia have RNA foci and differential alternative splicing; pmid:29526280 showed expansion-positive CEC lines have altered MBNL1/MBNL2/NUMA1 splicing and ASO-responsive rescue. |
| Functional Alteration | Patient cells | PMID:25593321 | 0.5 | FECD patient corneal endothelial tissue/cells with CTG18.1 expansion showed poly(CUG) RNA foci, MBNL1 co-localization/sequestration, and missplicing; expansion-negative FECD cells lacked these findings. |
| Functional Alteration | Patient cells | PMID:25168903 | 0.5 | |
| Functional Alteration | Non-patient cells | PMID:25593321 | 0.5 | Control corneal endothelial cells and expansion-negative FECD cells were used as comparators; RNA foci and missplicing were not observed in non-expanded/control cells. |
| Functional Alteration | Non-patient cells | PMID:24255041 | 0.5 | |
| Functional Alteration | Non-patient cells | PMID:25168903 | 0.5 | |
| Models | Non-human model organism | PMID:37169279 | 2 | UVA-induced FECD mouse model showed corneal endothelial damage and downregulation of mtDNA repair genes Lig3, Neil2, and Top3a; model is not TCF4 CTG repeat-expansion specific. |
| Rescue | Rescue in cell culture | PMID:29526280 | 1 | In six expansion-positive FECD CEC lines, (CAG)7 ASO reduced CUG RNA foci; in four lines it reduced MBNL1-positive puncta, and in ten lines it shifted MBNL1/MBNL2/NUMA1 splicing toward control patterns. |
10 rows
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.