Liu Yaoming, Li Gen, Jiang Jiaxuan, Fan Sujie, Lu Lan, Wang Ting, Li Guigang, Zhou Wenzong, Liu Xuequn, Li Yingjie, Sun Hong, Liang Liang, Tang Yuhong, Chen Yang, Gu Jianjun, Li Fei, Fang Xiuli, Sun Tao, Lv Aiguo, Wang Yayi, Wang Peiyuan, Wen Tao, Deng Jiayu, Liu Yuhong, Lai Mingying, Yu Jingni, Liu Danyan, Wang Hua, Chen Meizhu, Li Li, Huang Xiaodan, Shi Jingming, Zhang Xu, Zhang Kang, Liang Lingyi, Zhang Xiulan
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong 510060, China.
Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China.
Genes Dis. 2024 Nov 6;12(3):101448. doi: 10.1016/j.gendis.2024.101448. eCollection 2025 May.
Iridocorneal endothelial (ICE) syndrome is a rare, irreversibly blinding eye disease with an unknown etiology. Understanding its genomic and epigenomic landscape could aid in developing etiology-based therapies. In this study, we recruited 99 ICE patients and performed whole-genome sequencing (WGS) on 51 and genome-wide DNA methylation profiling on 48 of them. We conducted mutational burden testing on genes and noncoding regulatory regions, comparing the ICE cohort with control groups (9197 East Asians from the gnomAD database and 350 normal Chinese from our in-house cohort). Copy number variation (CNV) analysis and differential methylation of regions were also explored. We identified RP1L1 (27/51, 53%) with a significantly higher coding-altering mutational burden in the ICE cohort (p < 8.3×10), with mutations predominantly at chr8:10467637 (hg19). Additionally, 41 regions with significant CNVs were identified, including two regions at chr19:15783859-15791329 (hg19) and chr3:75786061-75790887 (hg19), showing copy number loss in 39 and 19 patients, respectively. We also identified 2,717 differentially methylated regions (DMRs), with hypomethylation prevalent in ICE syndrome (91.9% of DMRs). Among these, 45 recurrent hypomethylated regions (HMRs) in more than 10% of ICE patients showed differential methylation compared to normal controls. This study presents the first comprehensive genomic and epigenomic characterization of ICE syndrome, offering insights into its underlying etiology.
虹膜角膜内皮（ICE）综合征是一种病因不明的罕见、不可逆致盲眼病。了解其基因组和表观基因组特征有助于开发基于病因的治疗方法。在本研究中，我们招募了99例ICE患者，对其中51例进行了全基因组测序（WGS），对48例进行了全基因组DNA甲基化分析。我们对基因和非编码调控区域进行了突变负担测试，将ICE队列与对照组（来自gnomAD数据库的9197名东亚人和我们内部队列中的350名正常中国人）进行比较。还探索了拷贝数变异（CNV）分析和区域差异甲基化。我们在ICE队列中发现RP1L1（27/51，53%）的编码改变突变负担显著更高（p < 8.3×10），突变主要位于chr8:10467637（hg19）。此外，鉴定出41个具有显著CNV的区域，包括chr19:15783859 - 15791329（hg19）和chr3:75786061 - 75790887（hg19）的两个区域，分别在39例和19例患者中显示拷贝数缺失。我们还鉴定出2717个差异甲基化区域（DMR），ICE综合征中普遍存在低甲基化（91.9%的DMR）。其中，45个在超过10%的ICE患者中反复出现的低甲基化区域（HMR）与正常对照相比显示出差异甲基化。本研究首次对ICE综合征进行了全面的基因组和表观基因组特征分析，为其潜在病因提供了见解。
