Disease Expression and Familial Transmission of Fuchs Endothelial Corneal Dystrophy With and Without CTG18.1 Expansion

Xu, Timothy T.; Li, Yi-Ju; Afshari, Natalie A.; Aleff, Ross A.; Rinkoski, Tommy A.; Patel, Sanjay; Maguire, Leo J.; Edwards, Albert O.; Brown, William L.; Fautsch, Michael P.; Wieben, Eric D.; Baratz, Keith H.

doi:10.1167/iovs.62.1.17

Cited by 7 publications

(5 citation statements)

References 41 publications

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“…These limitations likely contributed to our underrepresentation of FECD diagnoses, which was 1.1% of patients in the current study compared with approximately 5% in the general population. 5,6 However, this finding was not surprising; we did not expect to identify most of the FECD cases because many FECD cases are mild, asymptomatic, underdiagnosed, and do not require frequent follow-up visits. Rather, this study was designed to evaluate an association between diagnoses and not incidence or prevalence rates of disease.…”

Section: Discussionmentioning

confidence: 98%

“…3,4 CTG18.1 expansion–associated FECD is inherited in an autosomal dominant pattern with incomplete penetrance and variable expressivity, with a predisposition toward women and individuals of northern European ancestry. 5 The prevalence of FECD is approximately 5% in the US population; thus, FECD is the most common TNR expansion disorder. 3,6…”

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confidence: 99%

“…3,4 CTG18.1 expansion-associated FECD is inherited in an autosomal dominant pattern with incomplete penetrance and variable expressivity, with a predisposition toward women and individuals of northern European ancestry. 5 The prevalence of FECD is approximately 5% in the US population; thus, FECD is the most common TNR expansion disorder. 3,6 Despite recent advancements in our understanding of FECD pathogenesis, it is unknown whether patients with FECD are at variable risk of systemic disease such as malignancy.…”

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confidence: 99%

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Cancer Risk in Patients With Fuchs Endothelial Corneal Dystrophy

Baratz

Fautsch

et al. 2021

Cornea

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The purpose of this study is to quantify cancer risk in patients with Fuchs endothelial corneal dystrophy (FECD). Methods:Using the 2014 to 2016 Medicare Limited 5% Data Sets -Carrier Line File, US Medicare fee-for-service beneficiaries (aged 65 years or older) with FECD and cancer were identified through International Classification of Diseases, ninth and 10th Revision diagnostic codes from January 1, 2014, to December 31, 2016. The main outcome measures were odds ratios (ORs) of cancer at various anatomic locations in patients with versus without FECD. Results: Of the 1,462,740 Medicare beneficiaries, 15,534 patients (1.1%) had an International Classification of Disease code for FECD. Compared with US Medicare beneficiaries without FECD, patients with FECD were at increased risk for the following malignancies: breast [

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Section: Discussionmentioning

confidence: 98%

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confidence: 99%

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confidence: 99%

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Cancer Risk in Patients With Fuchs Endothelial Corneal Dystrophy

Baratz

Fautsch

et al. 2021

Cornea

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“…The single-nucleotide polymorphism (SNP) rs613872 in the TCF4 gene is the most studied association marker of the late-onset FECD and its association was significant in several studies and in the meta-analysis (30,(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56). The CTG18.1 trinucleotide repeat expansion in the TCF4 gene has been detected in a large proportion of late-onset FECD patients and segregated in familial cases, so it is currently considered a causal variant (30,45,48,50,51,55,(57)(58)(59)(60)(61)(62)(63)(64). Its discovery by Wieben and co-authors was a breakthrough in understanding the genetics of late-onset FECD (57).…”

Section: Introductionmentioning

confidence: 99%

Systematic review of SLC4A11, ZEB1, LOXHD1, and AGBL1 variants in the development of Fuchs’ endothelial corneal dystrophy

Tsedilina,

Sharova,

Iakovets

et al. 2023

Front. Med.

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IntroductionThe pathogenic role of variants in TCF4 and COL8A2 in causing Fuchs’ endothelial corneal dystrophy (FECD) is not controversial and has been confirmed by numerous studies. The causal role of other genes, SLC4A11, ZEB1, LOXHD1, and AGBL1, which have been reported to be associated with FECD, is more complicated and less obvious. We performed a systematic review of the variants in the above-mentioned genes in FECD cases, taking into account the currently available population frequency information, transcriptomic data, and the results of functional studies to assess their pathogenicity.MethodsSearch for articles published in 2005–2022 was performed manually between July 2022 and February 2023. We searched for original research articles in peer-reviewed journals, written in English. Variants in the genes of interest identified in patients with FECD were extracted for the analysis. We classified each presented variant by pathogenicity status according to the ACMG criteria implemented in the Varsome tool. Diagnosis, segregation data, presence of affected relatives, functional analysis results, and gene expression in the corneal endothelium were taken into account. Data on the expression of genes of interest in the corneal endothelium were extracted from articles in which transcriptome analysis was performed. The identification of at least one variant in a gene classified as pathogenic or significantly associated with FECD was required to confirm the causal role of the gene in FECD.ResultsThe analysis included 34 articles with 102 unique ZEB1 variants, 20 articles with 64 SLC4A11 variants, six articles with 26 LOXHD1 variants, and five articles with four AGBL1 variants. Pathogenic status was confirmed for seven SLC4A11 variants found in FECD. No variants in ZEB1, LOXHD1, and AGBL1 genes were classified as pathogenic for FECD. According to the transcriptome data, AGBL1 and LOXHD1 were not expressed in the corneal endothelium. Functional evidence for the association of LOXHD1, and AGBL1 with FECD was conflicting.ConclusionOur analysis confirmed the causal role of SLC4A11 variants in the development of FECD. The causal role of ZEB1, LOXHD1, and AGBL1 variants in FECD has not been confirmed. Further evidence from familial cases and functional analysis is needed to confirm their causal roles in FECD.

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“…Most subjects without FECD have between 12 and 40 repeats of a CTG sequence in the third intron of TCF4 . In 77.7% of FECD cases in the United States, the CTG repeat sequence measured in peripheral blood leukocytes contains 50 to 3000 repeats (150 to 9000 bp) [ 1 ]. Our prior work in corneal tissue established that FECD associated with CTG repeat expansion in TCF4 (identified in peripheral blood leukocytes) leads to numerous changes in the transcriptome of FECD corneal endothelial cells, including hundreds of alterations in RNA splicing [ 2 – 4 ].…”

Section: Introductionmentioning

confidence: 99%

Comparison of TCF4 repeat expansion length in corneal endothelium and leukocytes of patients with Fuchs endothelial corneal dystrophy

et al. 2021

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Expansion of CTG trinucleotide repeats (TNR) in the transcription factor 4 (TCF4) gene is highly associated with Fuchs Endothelial Corneal Dystrophy (FECD). Due to limitations in the availability of DNA from diseased corneal endothelium, sizing of CTG repeats in FECD patients has typically been determined using DNA samples isolated from peripheral blood leukocytes. However, it is non-feasible to extract enough DNA from surgically isolated FECD corneal endothelial tissue to determine repeat length based on current technology. To circumvent this issue, total RNA was isolated from FECD corneal endothelium and sequenced using long-read sequencing. Southern blotting of DNA samples isolated from primary cultures of corneal endothelium from these same affected individuals was also assessed. Both long read sequencing and Southern blot analysis showed significantly longer CTG TNR expansion (>1000 repeats) in the corneal endothelium from FECD patients than those characterized in leukocytes from the same individuals (<90 repeats). Our findings suggest that the TCF4 CTG repeat expansions in the FECD corneal endothelium are much longer than those found in leukocytes.

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Disease Expression and Familial Transmission of Fuchs Endothelial Corneal Dystrophy With and Without CTG18.1 Expansion

Cited by 7 publications

References 41 publications

Cancer Risk in Patients With Fuchs Endothelial Corneal Dystrophy

Cancer Risk in Patients With Fuchs Endothelial Corneal Dystrophy

Systematic review of SLC4A11, ZEB1, LOXHD1, and AGBL1 variants in the development of Fuchs’ endothelial corneal dystrophy

Comparison of TCF4 repeat expansion length in corneal endothelium and leukocytes of patients with Fuchs endothelial corneal dystrophy

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