Siyin Liu, Amanda N. Sadan, Nihar Bhattacharyya, Christina Zarouchlioti, Anita Szabo, Marcos Abreu Costa, Nathaniel J. Hafford-Tear, Anne-Marie S. Kladny, Lubica Dudakova, Marc Ciosi, Ismail Moghul, Mark R. Wilkins, Bruce Allan, Pavlina Skalicka, Alison J. Hardcastle, Nikolas Pontikos, Catey Bunce, Darren G. Monckton, Kirithika Muthusamy, Petra Liskova, Stephen J. Tuft, Alice E. Davidson
{"title":"Genetic and Demographic Determinants of Fuchs Endothelial Corneal Dystrophy Risk and Severity","authors":"Siyin Liu, Amanda N. Sadan, Nihar Bhattacharyya, Christina Zarouchlioti, Anita Szabo, Marcos Abreu Costa, Nathaniel J. Hafford-Tear, Anne-Marie S. Kladny, Lubica Dudakova, Marc Ciosi, Ismail Moghul, Mark R. Wilkins, Bruce Allan, Pavlina Skalicka, Alison J. Hardcastle, Nikolas Pontikos, Catey Bunce, Darren G. Monckton, Kirithika Muthusamy, Petra Liskova, Stephen J. Tuft, Alice E. Davidson","doi":"10.1001/jamaophthalmol.2025.0109","DOIUrl":null,"url":null,"abstract":"ImportanceUnderstanding the pathogenic mechanisms of Fuchs endothelial corneal dystrophy (FECD) could contribute to developing gene-targeted therapies.ObjectiveTo investigate associations between demographic data and age at first keratoplasty in a genetically refined FECD cohort.Design, Setting, and ParticipantsThis 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 (≥50 repeats) were classified as expansion-positive (Exp+). Expansion-negative (Exp-) cases were exome sequenced.Main Outcomes and MeasuresAssociation between variants in FECD-associated genes, demographic data, and age at first keratoplasty.ResultsWithin 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%; <jats:italic>P</jats:italic> &amp;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; <jats:italic>P</jats:italic> &amp;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; <jats:italic>P</jats:italic> = .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; <jats:italic>P</jats:italic> &amp;lt; .001), indicating that 2 Exp+ alleles were associated with increased disease penetrance compared with 1 expansion. Potentially pathogenic variants (minor allele frequency, &amp;lt;0.01; combined annotation dependent depletion, &amp;gt;15) were only identified in FECD-associated genes in 13 Exp- individuals (10.1%).Conclusions and RelevanceIn 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.","PeriodicalId":14518,"journal":{"name":"JAMA ophthalmology","volume":"213 1","pages":""},"PeriodicalIF":7.8000,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JAMA ophthalmology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1001/jamaophthalmol.2025.0109","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
ImportanceUnderstanding the pathogenic mechanisms of Fuchs endothelial corneal dystrophy (FECD) could contribute to developing gene-targeted therapies.ObjectiveTo investigate associations between demographic data and age at first keratoplasty in a genetically refined FECD cohort.Design, Setting, and ParticipantsThis 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 (≥50 repeats) were classified as expansion-positive (Exp+). Expansion-negative (Exp-) cases were exome sequenced.Main Outcomes and MeasuresAssociation between variants in FECD-associated genes, demographic data, and age at first keratoplasty.ResultsWithin 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 RelevanceIn 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.
期刊介绍:
JAMA Ophthalmology, with a rich history of continuous publication since 1869, stands as a distinguished international, peer-reviewed journal dedicated to ophthalmology and visual science. In 2019, the journal proudly commemorated 150 years of uninterrupted service to the field. As a member of the esteemed JAMA Network, a consortium renowned for its peer-reviewed general medical and specialty publications, JAMA Ophthalmology upholds the highest standards of excellence in disseminating cutting-edge research and insights. Join us in celebrating our legacy and advancing the frontiers of ophthalmology and visual science.