FECD3 TCF4

Late-onset Fuchs endothelial corneal dystrophy (FECD) is a degenerative disorder ... distinguished from other corneal disorders by the progressive formation of guttae¹. Studies suggest that disease severity increases in women with greater lifetime exposure to oestrogen².

Prevalence

4.5 100

~4/100 (over 40)¹; 5/100³. Predominantly in women (~75%)⁴. In one study of two cohorts (Dallas Heart Study and 1000 Genomes Project), expanded allele carrier rates were 3.1% (African American), 8.1% (European American), and 3.3% (Latinos)in DHS, and 2.7% (AFR), 9.5% (EUR), 5.2% (East Asians), 7.2% (South Asians), and 5.2% (admixed Americans) in 1KGP⁵. The highest carrier prevalence (12.1%–12.5%) occurred in EUR and admixed American subpopulations, while rates were 0%–1.9% in West Africans vs 6.2% in a Kenyan subpopulation.

Age of Onset Details

Typical: 40-59⁶; Range: 32⁷- 79⁸.

Locus

hg19

chr18:53253384-53253460

hg38

chr18:55586153-55586229

t2t

chr18:55789233-55789288

Details

Most controls have <40 repeats while majority of patients have >50 repeats; penetrance is <100%, as unaffected individuals have been documented with >80 repeats and alleles of affected individuals range from 12-2600^9,10. Expansions are causative in approximately 70% of disease cases⁹.

Mechanism

GoF

Sequestration of MBNL1 in RNA foci, similar to the mechanism underlying myotonic dystrophy-1¹¹. Variation in RAN translation¹².

Year

2012¹³

Location in Gene

Intron 1

Gene Strand

Alleles

Ref. Motif

CAG

Pathogenic (ref.)

CAG

Pathogenic (gene)

CTG

gnomAD

References

Direct supporting references for info on this page.

omim:613267

Associations between measures of oestrogen exposure and severity of Fuchs endothelial corneal dystrophy.

Redion B,Petrela, Chandra Divyash,Chhetri, Ahmad,Najafi, Zhaoqi,Zhang, Tommy,A Rinkoski, Eric D,Wieben, Michael P,Fautsch, Saptarshi,Chakraborty, Amy,E Millen, Sangita P,Patel

BMJ open ophthalmology · 2025-05-14

pmid:40374208

E2-2 protein and Fuchs's corneal dystrophy.

Keith H,Baratz, Nirubol,Tosakulwong, Euijung,Ryu, William L,Brown, Kari,Branham, Wei,Chen, Khoa D,Tran, Katharina E,Schmid-Kubista, John R,Heckenlively, Anand,Swaroop, Goncalo,Abecasis, Kent R,Bailey, Albert O,Edwards

The New England journal of medicine · 2010-08-25

pmid:20825314

Clinical study of Fuchs corneal endothelial dystrophy leading to penetrating keratoplasty: a 30-year experience.

Natalie A,Afshari, Aaron B,Pittard, Adnan,Siddiqui, Gordon K,Klintworth

Archives of ophthalmology (Chicago, Ill. : 1960) · 2006-06-01

pmid:16769829

Prevalence of Transcription Factor 4 Gene Triplet Repeat Expansion Associated with Fuchs' Endothelial Corneal Dystrophy in the United States and Global Populations.

Xunzhi,Zhang, Ashwani,Kumar, Xin,Gong, Chao,Xing, V Vinod,Mootha

Ophthalmology science · 2024-08-30

pmid:39669694

Pharmacological profile of non-hydroxylated and ether derivatives of the potent D2-selective agonist N-0437.

J M,Jansen, I,den Daas, H,Rollema, P J,Swart, P G,Tepper, J B,de Vries, A S,Horn

Naunyn-Schmiedeberg's archives of pharmacology · 1991-02-01

pmid:1676829

Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus.

S Amer,Riazuddin, Elyse J,McGlumphy, William S,Yeo, Jiangxia,Wang, Nicholas,Katsanis, John D,Gottsch

Investigative ophthalmology & visual science · 2011-04-27

pmid:21245398

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

Tatsuya,Nakagawa, Yuichi,Tokuda, Masakazu,Nakano, Ayana,Tateishi, Mari,Yasunaga, Theofilos,Tourtas, Ursula,Schlötzer-Schrehardt, Friedrich,Kruse, Kei,Tashiro, Noriko,Koizumi, Naoki,Okumura

Cornea · 2025-02-25

pmid:39998965

Resources for Genetics Professionals — Genetic Disorders Caused by Nucleotide Repeat Expansions and Contractions

Stephanie E.,Wallace, Lora JH,Bean

GeneReviews® [Internet] · 2022-10-20

genereviews:NBK535148

Comprehensive assessment of genetic variants within TCF4 in Fuchs' endothelial corneal dystrophy.

Eric D,Wieben, Ross A,Aleff, Bruce W,Eckloff, Elizabeth J,Atkinson, Saurabh,Baheti, Sumit,Middha, William L,Brown, Sanjay V,Patel, Jean-Pierre A,Kocher, Keith H,Baratz

Investigative ophthalmology & visual science · 2014-08-28

pmid:25168903

RNA toxicity and missplicing in the common eye disease fuchs endothelial corneal dystrophy.

Jintang,Du, Ross A,Aleff, Elisabetta,Soragni, Krishna,Kalari, Jinfu,Nie, Xiaojia,Tang, Jaime,Davila, Jean-Pierre,Kocher, Sanjay V,Patel, Joel M,Gottesfeld, Keith H,Baratz, Eric D,Wieben

The Journal of biological chemistry · 2015-01-15

pmid:25593321

Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications.

Indhu-Shree,Rajan-Babu, Egor,Dolzhenko, Michael A,Eberle, Jan M,Friedman

Nature reviews. Genetics · 2024-03-11

pmid:38467784

A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy.

Eric D,Wieben, Ross A,Aleff, Nirubol,Tosakulwong, Malinda L,Butz, W Edward,Highsmith, Albert O,Edwards, Keith H,Baratz

PloS one · 2012-11-21

pmid:23185296

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Association of Non-Coding Repeat Expansions with Parkinson's Disease Risk: Evidence from a UK Biobank-Based Whole-Genome Sequencing Study.

Zhen,Hu, Qin-Qin,Yan, Jing-Jin,Wan, Yu,Fan, Jun,Liu

Movement disorders : official journal of the Movement Disorder Society · 2025-10-11

pmid:41074692

Transcriptomic analysis implicates the involvement of RBM20 in Fuchs' endothelial corneal dystrophy with TCF4 repeat expansion.

Xunzhi,Zhang, Ze,Yu, Aundrea K,Westfall, Kunyi,Han, V Vinod,Mootha, Chao,Xing

PloS one · 2025-09-17

pmid:40961119

Rare variants in MIR184 are a novel genetic cause of Fuchs endothelial corneal dystrophy.

Marcos,Abreu Costa, Amanda N,Sadan, Nihar,Bhattacharyya, Niuzheng,Chai, Christina,Zarouchlioti, Siyin,Liu, Anita,Szabo, Cian,Murphy, Lubica,Dudakova, Kirithika,Muthusamy, Pavlina,Skalicka, Ismail,Moghul, Nikolas,Pontikos, Petra,Liskova, Stephen J,Tuft, Alice E,Davidson

Genetics in medicine : official journal of the American College of Medical Genetics · 2025-08-21

pmid:40852795

Repeat Expansion and Somatic Instability in TCF4 in Patients With Fuchs Endothelial Corneal Dystrophy Identified by Small Pool PCR.

Sayo,Maeno, Arisa,Yamashita, Yoshinori,Oie, Ryota,Koto, Chifune,Kai, Nozomi,Nishida, Masayuki,Nakamori, Motokazu,Tsujikawa, Kohji,Nishida

Investigative ophthalmology & visual science · 2025-08-01

pmid:40767442

Long-Range PCR and Nanopore Sequencing Enables High-Throughput Detection of TCF4 Trinucleotide Repeat Expansions in Fuchs Endothelial Corneal Dystrophy.

Bushra,Alayed, Salina,Siddiqui, Seema,Anand, Chris F,Inglehearn, Christopher M,Watson, Manir,Ali

Molecular diagnosis & therapy · 2025-07-28

pmid:40720054

Reanalysis of Next-Generation Sequencing Data to Detect Tandem Repeat Expansions in 1,106 Czech Probands With Neurologic Disease.

Alena,Musilova, Petra,Lassuthova, Anna,Uhrova Meszarosova, Barbora,Straka, Jana,Krejcikova, Anna,Berounska, Marketa,Vlckova, Zuzana,Musova, Dana,Safka Brozkova

Neurology. Genetics · 2025-06-25

pmid:40585427

TCF4 expansion-associated loss of FN1 intron retention drives extracellular matrix accumulation in Fuchs endothelial corneal dystrophy.

Soichiro,Inagaki, Taichi,Yuasa, Theofilos,Tourtas, Ursula,Schlötzer-Schrehardt, Friedrich,Kruse, Noriko,Koizumi, Naoki,Okumura

Experimental eye research · 2025-04-21

pmid:40268158

Involvement of TGF-β signaling pathway-associated genes in the corneal endothelium of patients with Fuchs endothelial corneal dystrophy.

Tatsuya,Nakagawa, Tetsuro,Honda, Soichiro,Inagaki, Taichi,Yuasa, Theofilos,Tourtas, Ursula,Schlötzer-Schrehardt, Friedrich,Kruse, Ines,Aouimeur, Hanielle,Vaitinadapoule, Gauthier,Travers, Zhiguo,He, Philippe,Gain, Noriko,Koizumi, Gilles,Thuret, Naoki,Okumura

Experimental eye research · 2025-03-11

pmid:40081749

The TCF4 Gene Regulates Apoptosis of Corneal Endothelial Cells in Fuchs Endothelial Corneal Dystrophy.

Tatsuya,Nakagawa, Tetsuro,Honda, Taichi,Yuasa, Go,Nishiuchi, Masakazu,Sato, Ayumi,Tokunaga, Makiko,Nakahara, Theofilos,Tourtas, Ursula,Schlötzer-Schrehardt, Friedrich,Kruse, Prema,Padmanabhan, Amit,Chatterjee, Gajanan,Sathe, Vivek,Ghose, Narayanan,Janakiraman, Derek J,Blake, Noriko,Koizumi, Sailaja,Elchuri, Naoki,Okumura

Investigative ophthalmology & visual science · 2025-03-03

pmid:40048186