The genomic and epigenomic landscape of iridocorneal endothelial syndrome

The iridocorneal endothelial (ICE) syndrome is a rare but irreversibly blinding eye disease, whose etiology remains unknown and speculative. Characterization of its genomic and epigenomic landscape will benefit the development of etiology-based therapies. In this study, we recruited a cohort of 99 patients with ICE syndrome. Whole-genome sequencing was performed on 51 ICE patients and genome-wide DNA methylation profiling on 48 ICE patients. We then performed the mutational burden testing on genes and noncoding regulatory regions in the ICE cohort compared with control subjects (including 9197 East Asians from the gnomAD database and 350 normal Chinese from our in-house cohort). Copy number variance analysis was also performed. Hypomethylated and differentially methylated regions in ICE patients versus normal controls (45 normal Chinese from our in-house cohort) were explored. We identified RP1L1 (27/51, 53%) which emerged with a higher coding-altering mutational burden in the ICE syndrome cohort, whose mutations were mainly on chr8:10467637. We identified 41 regions exhibiting significant copy number variance. Specifically, regions at chr19:15783859-15791329 and chr3:75786061-75790887 showcased copy number loss in 39 and 19 out of 51 ICE patients, respectively. We also identified that 2717 differentially methylated regions and hypomethylation regions were predominantly found in ICE syndrome compared with normal samples (in 91.9% of 2717 differentially methylated regions). We also found 45 recurrent hypomethylation regions (identified in >10% ICE samples tested) that were differentially methylated (differential methylation < −0.1) between ICE syndrome and normal Chinese. Our study offers the first comprehensive genomic and epigenomic landscape of ICE syndrome, which will enhance the understanding of its etiology.