Evidence map›Paper›PMID 39278108›Full record

ArticleEBioMedicine2024

Tissue-specific TCF4 triplet repeat instability revealed by optical genome mapping.

Christina Zarouchlioti, Stephanie Efthymiou, Stefano Facchini, Natalia Dominik, Nihar Bhattacharyya, Siyin Liu, Marcos Abreu Costa, Anita Szabo, Amanda N Sadan, Albert S Jun and 11 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in EBioMedicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.

0numbers the graph read from it
0cells of the map it votes in
14citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

14 citing papers in PubMed.

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  5. Longitudinal Study ofMedical sciences (Basel, Switzerland) · 2026
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors.

Christina ZarouchliotiUCL Institute of Ophthalmology, London, UK.
Stephanie EfthymiouUCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK.
Stefano FacchiniUCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK.
Natalia DominikUCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK.
Nihar BhattacharyyaUCL Institute of Ophthalmology, London, UK.
Siyin LiuUCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK.
Marcos Abreu CostaUCL Institute of Ophthalmology, London, UK.
Anita SzaboUCL Institute of Ophthalmology, London, UK.
Amanda N SadanUCL Institute of Ophthalmology, London, UK.
Albert S JunCornea, Cataract, and External Disease Division, Wilmer Eye Institute, Johns Hopkins Medicine, Baltimore, USA.
Enrico BugiardiniUCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK.
Henry HouldenUCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK.
Andrea CorteseUCL Queen Square Institute of Neurology, Department of Neuromuscular Diseases, London, UK.
Pavlina SkalickaDepartment of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Lubica DudakovaDepartment of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Kirithika MuthusamyMoorfields Eye Hospital, London, UK.
Michael E CheethamUCL Institute of Ophthalmology, London, UK.
Alison J HardcastleUCL Institute of Ophthalmology, London, UK.
Petra LiskovaDepartment of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Stephen J TuftUCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK.
Alice E DavidsonUCL Institute of Ophthalmology, London, UK; Moorfields Eye Hospital, London, UK. Electronic address: alice.davidson@ucl.ac.uk.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundFuchs endothelial corneal dystrophy (FECD) is the most common repeat-mediated disease in humans. It exclusively affects corneal endothelial cells (CECs), with ≤81% of cases associated with an intronic TCF4 triplet repeat (CTG18.1). Here, we utilise optical genome mapping (OGM) to investigate CTG18.1 tissue-specific instability to gain mechanistic insights.

methodsWe applied OGM to a diverse range of genomic DNAs (gDNAs) from patients with FECD and controls (n = 43); CECs, leukocytes and fibroblasts. A bioinformatics pipeline was developed to robustly interrogate CTG18.1-spanning DNA molecules. All results were compared with conventional polymerase chain reaction-based fragment analysis.

findingsAnalysis of bio-samples revealed that expanded CTG18.1 alleles behave dynamically, regardless of cell-type origin. However, clusters of CTG18.1 molecules, encompassing ∼1800-11,900 repeats, were exclusively detected in diseased CECs from expansion-positive cases. Additionally, both progenitor allele size and age were found to influence the level of leukocyte-specific CTG18.1 instability.

interpretationOGM is a powerful tool for analysing somatic instability of repeat loci and reveals here the extreme levels of CTG18.1 instability occurring within diseased CECs underpinning FECD pathophysiology, opening up new therapeutic avenues for FECD. Furthermore, these findings highlight the broader translational utility of FECD as a model for developing therapeutic strategies for rarer diseases similarly attributed to somatically unstable repeats.

fundingUK Research and Innovation, Moorfields Eye Charity, Fight for Sight, Medical Research Council, NIHR BRC at Moorfields Eye Hospital and UCL Institute of Ophthalmology, Grantová Agentura České Republiky, Univerzita Karlova v Praze, the National Brain Appeal's Innovation Fund and Rosetrees Trust.

Indexed as

Fuchs' Endothelial DystrophyTranscription Factor 4AgedAllelesChromosome MappingFemaleGenomic InstabilityHumansMaleMiddle AgedOrgan SpecificityTrinucleotide Repeat ExpansionTrinucleotide RepeatsTCF4 protein, humanTranscription Factor 4Fuchs endothelial corneal dystrophyOptical genome mappingSomatic mosaicismTissue-specific repeat instabilityTrinucleotide repeat expansion diseaseTriplet repeat expansion-mediated disease

Identifiers

PMID39278108
PMCPMC11419830

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.