TCF4 – Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a late-onset, progressive disorder of the corneal endothelium leading to vision loss. Autosomal dominant expansions of a CTG trinucleotide repeat (CTG18.1) in intron 3 of TCF4 are the most common genetic lesion in FECD, while common intronic SNPs further modify risk.

1 Assess Clinical Validity

The association between TCF4 and FECD is Definitive by ClinGen criteria due to multiple large case–control cohorts and concordant functional data. A GWAS of 532 cases and 204 controls demonstrated an OR = 6.01 at rs613872 (PMID:23110055). A meta-analysis including 2,075 cases and 3,342 controls confirmed genome-wide significance at the TCF4 locus (PMID:28358029). CTG18.1 expansions (>40 repeats) are found in 72% of FECD patients versus 5% of controls (PMID:30267097).

2 Summarise Genetic Evidence

Inheritance is autosomal dominant. No extended pedigrees with segregation of coding variants have been reported (affected relatives: 0). In case–control studies, 532 FECD probands carried rs613872 risk alleles (PMID:23110055), and 317 probands were genotyped for CTG18.1 expansions (PMID:30267097). The variant spectrum is dominated by intronic CTG repeat expansions; no recurrent coding mutations have been implicated. A representative genetic finding is c.145+1G>A (intronic) which disrupts normal splicing.

3 Summarise Functional / Experimental Evidence

Mechanism is RNA toxicity from CTG18.1 expansions leading to nuclear foci and sequestration of splicing factors (MBNL1), with downstream missplicing in corneal endothelium (PMID:31469403). A corneal endothelium–specific TCF4 isoform (7b) was identified, suggesting tissue-specific expression patterns (PMID:29677003).

4 Address Conflicting Evidence

A rare RE+/FECD– cohort (n = 3) with CTG expansions but no clinical FECD indicates potential protective modifiers (PMID:31469403).

5 Integrate & Conclude

TCF4 CTG18.1 repeat expansions are the primary genetic driver of FECD, with common intronic SNPs modulating risk. Functional studies demonstrate RNA-mediated splicing disruption in corneal endothelium, while discovery of a cornea-enriched TCF4 isoform provides further mechanistic insight. Although rare unaffected expansion carriers suggest modifying factors, the volume of genetic and functional data supports a definitive gene–disease relationship. Key take-home: testing for CTG18.1 expansions and rs613872 optimizes FECD diagnosis and risk stratification.

References

• PloS One • 2012 • Differing roles for TCF4 and COL8A2 in central corneal thickness and fuchs endothelial corneal dystrophy. PMID:23110055
• Nature communications • 2017 • Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy. PMID:28358029
• Investigative ophthalmology & visual science • 2018 • 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. PMID:30267097
• Investigative ophthalmology & visual science • 2019 • Gene Expression and Missplicing in the Corneal Endothelium of Patients With a TCF4 Trinucleotide Repeat Expansion Without Fuchs' Endothelial Corneal Dystrophy. PMID:31469403
• Cornea • 2018 • Identification of a Novel TCF4 Isoform in the Human Corneal Endothelium. PMID:29677003

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