Genetic and Demographic Determinants of Fuchs Endothelial Corneal Dystrophy Risk and Severity

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F25%3A10497923" target="_blank" >RIV/00216208:11110/25:10497923 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00064165:_____/25:10497923

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=BBPnxxJ6xJ" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=BBPnxxJ6xJ</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1001/jamaophthalmol.2025.0109" target="_blank" >10.1001/jamaophthalmol.2025.0109</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Genetic and Demographic Determinants of Fuchs Endothelial Corneal Dystrophy Risk and Severity

Popis výsledku v původním jazyce

Importance: Understanding the pathogenic mechanisms of Fuchs endothelial corneal dystrophy (FECD) could contribute to developing gene-targeted therapies. Objective: To investigate associations between demographic data and age at first keratoplasty in a genetically refined FECD cohort. Design, Setting, and Participants: This retrospective cohort study recruited 894 individuals with FECD at Moorfields Eye Hospital (London) and General University Hospital (Prague) from September 2009 to July 2023. Ancestry was inferred from genome-wide single nucleotide polymorphism array data. CTG18.1 status was determined by short tandem repeat and/or triplet-primed polymerase chain reaction. One or more expanded alleles (&gt;=50 repeats) were classified as expansion-positive (Exp+). Expansion-negative (Exp-) cases were exome sequenced. Main Outcomes and Measures: Association between variants in FECD-associated genes, demographic data, and age at first keratoplasty. Results: Within the total cohort (n = 894), 77.3% of patients were Exp+. Most European (668 of 829 [80.6%]) and South Asian (14 of 22 [63.6%]) patients were Exp+. The percentage of female patients was higher (151 [74.4%]) in the Exp- cohort compared to the Exp+ cohort (395 [57.2%]; difference, 17.2%; 95% CI, 10.1%-24.3%; P &lt; .001). The median (IQR) age at first keratoplasty of the Exp + patients (68.2 years [63.2-73.6]) was older than the Exp- patients (61.3 years [52.6-70.4]; difference, 6.5 years; 95% CI, 3.4-9.7; P &lt; .001). The CTG18.1 repeat length of the largest expanded allele within the Exp+ group was inversely correlated with the age at first keratoplasty (β, -0.087; 95% CI, -0.162 to -0.012; P = .02). The ratio of biallelic to monoallelic expanded alleles was higher in the FECD cohort (1:14) compared to an unaffected control group (1:94; P &lt; .001), indicating that 2 Exp+ alleles were associated with increased disease penetrance compared with 1 expansion. Potentially pathogenic variants (minor allele frequency, &lt;0.01; combined annotation dependent depletion, &gt;15) were only identified in FECD-associated genes in 13 Exp- individuals (10.1%). Conclusions and Relevance: In this multicenter cohort study among individuals with FECD, CTG18.1 expansions were present in most European and South Asian patients, while CTG18.1 repeat length and zygosity status were associated with modifications in disease severity and penetrance. Known disease-associated genes accounted for only a minority of Exp- cases, with unknown risk factors associated with disease in the rest of this subgroup. These data may have implications for future FECD gene-targeted therapy development.

Název v anglickém jazyce

Genetic and Demographic Determinants of Fuchs Endothelial Corneal Dystrophy Risk and Severity

Popis výsledku anglicky

Importance: Understanding the pathogenic mechanisms of Fuchs endothelial corneal dystrophy (FECD) could contribute to developing gene-targeted therapies. Objective: To investigate associations between demographic data and age at first keratoplasty in a genetically refined FECD cohort. Design, Setting, and Participants: This retrospective cohort study recruited 894 individuals with FECD at Moorfields Eye Hospital (London) and General University Hospital (Prague) from September 2009 to July 2023. Ancestry was inferred from genome-wide single nucleotide polymorphism array data. CTG18.1 status was determined by short tandem repeat and/or triplet-primed polymerase chain reaction. One or more expanded alleles (&gt;=50 repeats) were classified as expansion-positive (Exp+). Expansion-negative (Exp-) cases were exome sequenced. Main Outcomes and Measures: Association between variants in FECD-associated genes, demographic data, and age at first keratoplasty. Results: Within the total cohort (n = 894), 77.3% of patients were Exp+. Most European (668 of 829 [80.6%]) and South Asian (14 of 22 [63.6%]) patients were Exp+. The percentage of female patients was higher (151 [74.4%]) in the Exp- cohort compared to the Exp+ cohort (395 [57.2%]; difference, 17.2%; 95% CI, 10.1%-24.3%; P &lt; .001). The median (IQR) age at first keratoplasty of the Exp + patients (68.2 years [63.2-73.6]) was older than the Exp- patients (61.3 years [52.6-70.4]; difference, 6.5 years; 95% CI, 3.4-9.7; P &lt; .001). The CTG18.1 repeat length of the largest expanded allele within the Exp+ group was inversely correlated with the age at first keratoplasty (β, -0.087; 95% CI, -0.162 to -0.012; P = .02). The ratio of biallelic to monoallelic expanded alleles was higher in the FECD cohort (1:14) compared to an unaffected control group (1:94; P &lt; .001), indicating that 2 Exp+ alleles were associated with increased disease penetrance compared with 1 expansion. Potentially pathogenic variants (minor allele frequency, &lt;0.01; combined annotation dependent depletion, &gt;15) were only identified in FECD-associated genes in 13 Exp- individuals (10.1%). Conclusions and Relevance: In this multicenter cohort study among individuals with FECD, CTG18.1 expansions were present in most European and South Asian patients, while CTG18.1 repeat length and zygosity status were associated with modifications in disease severity and penetrance. Known disease-associated genes accounted for only a minority of Exp- cases, with unknown risk factors associated with disease in the rest of this subgroup. These data may have implications for future FECD gene-targeted therapy development.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10600 - Biological sciences

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

JAMA Ophthalmology

ISSN

2168-6165

e-ISSN

2168-6173

Svazek periodika

143

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

10

Strana od-do

338-347

Kód UT WoS článku

001445047900001

EID výsledku v databázi Scopus

2-s2.0-105002301954