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Abstract：
Unilateral high myopia (uHM), commonly observed in patients with retinal diseases or only with high myopia, is frequently associated with amblyopia with poor prognosis. This study aims to reveal the clinical and genetic spectrum of uHM in a large Chinese cohort.
A total of 75 probands with simplex uHM were included in our Pediatric and Genetic Eye Clinic. Patients with significant posterior anomalies other than myopic fundus changes were excluded. Variants were detected by exome sequencing and then analyzed through multiple-step bioinformatic and co-segregation analysis and finally confirmed by Sanger sequencing. Genetic findings were correlated with associated clinical data for analysis.
Among the 75 probands with a mean age of 6.21 ± 4.70 years at the presentation, myopic fundus of C1 and C2 was observed in 73 (97.3%) probands. Surprisingly, specific peripheral changes were identified in 63 eyes involving 36 (48.0%) probands after extensive examination, including peripheral retinal avascular zone (74.6%, 47/63 eyes), neovascularization (54.0%), fluorescein leakage (31.7%), peripheral pigmentary changes (31.7%), and others. Exome sequencing identified 21 potential pathogenic variants of 13 genes in 20 of 75 (26.7%) probands, including genes for Stickler syndrome (COL11A1 and COL2A1; 6/20), FEVR (FZD4, LRP5, and TSPAN12; 5/20), and others (FBN1, GPR179, ZEB2, PAX6, GPR143, OPN1LW, FRMD7, and CACNA1F; 9/20). For the peripheral retinal changes in the 20 probands, variants in Stickler syndrome-related genes were predominantly associated with retinal pigmentary changes, lattice degeneration, and retinal avascular region, while variants in genes related to FEVR were mainly associated with the avascular zone, neovascularization, and fluorescein leakage.
Genetic defects were identified in about one-fourth of simplex uHM patients in which significant consequences may be hidden under a classic myopic fundus in up to half. To our knowledge, this is the first systematic genetic study on simplex uHM to date. In addition to routine care of strabismus and amblyopia, careful examination of the peripheral retina and genetic screening is warranted for patients with uHM in order to identify signs of risk for retinal detachment and other complications and provide meaningful genetic counseling.
A total of 75 probands with simplex uHM were included in our Pediatric and Genetic Eye Clinic. Patients with significant posterior anomalies other than myopic fundus changes were excluded. Variants were detected by exome sequencing and then analyzed through multiple-step bioinformatic and co-segregation analysis and finally confirmed by Sanger sequencing. Genetic findings were correlated with associated clinical data for analysis.
Among the 75 probands with a mean age of 6.21 ± 4.70 years at the presentation, myopic fundus of C1 and C2 was observed in 73 (97.3%) probands. Surprisingly, specific peripheral changes were identified in 63 eyes involving 36 (48.0%) probands after extensive examination, including peripheral retinal avascular zone (74.6%, 47/63 eyes), neovascularization (54.0%), fluorescein leakage (31.7%), peripheral pigmentary changes (31.7%), and others. Exome sequencing identified 21 potential pathogenic variants of 13 genes in 20 of 75 (26.7%) probands, including genes for Stickler syndrome (COL11A1 and COL2A1; 6/20), FEVR (FZD4, LRP5, and TSPAN12; 5/20), and others (FBN1, GPR179, ZEB2, PAX6, GPR143, OPN1LW, FRMD7, and CACNA1F; 9/20). For the peripheral retinal changes in the 20 probands, variants in Stickler syndrome-related genes were predominantly associated with retinal pigmentary changes, lattice degeneration, and retinal avascular region, while variants in genes related to FEVR were mainly associated with the avascular zone, neovascularization, and fluorescein leakage.
Genetic defects were identified in about one-fourth of simplex uHM patients in which significant consequences may be hidden under a classic myopic fundus in up to half. To our knowledge, this is the first systematic genetic study on simplex uHM to date. In addition to routine care of strabismus and amblyopia, careful examination of the peripheral retina and genetic screening is warranted for patients with uHM in order to identify signs of risk for retinal detachment and other complications and provide meaningful genetic counseling.
摘要：
背景：单侧高度近视（uHM），常见于视网膜疾病患者或仅高度近视患者，常伴有弱视，预后不良。这项研究旨在揭示一个大型中国队列中uHM的临床和遗传谱。
方法：我们的儿科和遗传眼科诊所共纳入了75位单纯性uHM先证者。除近视眼底改变外，具有明显后部异常的患者被排除在外。通过外显子组测序检测变异，然后通过多步生物信息学和共分离分析进行分析，最后通过Sanger测序进行确认。遗传结果与相关的临床数据进行关联分析。
结果：在陈述时平均年龄为6.21±4.70岁的75位先证者中，在73位（97.3％）先证者中观察到C1和C2的近视眼底。令人惊讶的是,在广泛检查后，在63只眼中发现了特定的外周变化，涉及36（48.0％）先证者，包括周边视网膜无血管区（74.6%，47/63眼），新生血管（54.0%），荧光素渗漏（31.7%），外周色素变化（31.7%），和其他人。外显子组测序在75个先证者中的20个（26.7％）中鉴定出13个基因的21个潜在致病变体，包括Stickler综合征的基因（COL11A1和COL2A1;6/20），FEVR（FZD4、LRP5和TSPAN12；5/20），和其他(FBN1、GPR179、ZEB2、PAX6、GPR143、OPN1LW、FRMD7和CACNA1F；9/20）。对于20位先证者的周边视网膜变化，Stickler综合征相关基因的变异主要与视网膜色素变化相关，晶格退化，和视网膜无血管区域，而与FEVR相关的基因变异主要与无血管区相关，新生血管形成,和荧光素泄漏。
结论：在约四分之一的单纯性uHM患者中发现了遗传缺陷，其中在经典近视眼底下可能隐藏了多达一半的明显后果。据我们所知,这是迄今为止对单纯形uHM的第一个系统的遗传研究。除了斜视和弱视的常规护理，uHM患者需要对周边视网膜进行仔细检查和基因筛查,以确定视网膜脱离和其他并发症的风险迹象,并提供有意义的遗传咨询.
方法：我们的儿科和遗传眼科诊所共纳入了75位单纯性uHM先证者。除近视眼底改变外，具有明显后部异常的患者被排除在外。通过外显子组测序检测变异，然后通过多步生物信息学和共分离分析进行分析，最后通过Sanger测序进行确认。遗传结果与相关的临床数据进行关联分析。
结果：在陈述时平均年龄为6.21±4.70岁的75位先证者中，在73位（97.3％）先证者中观察到C1和C2的近视眼底。令人惊讶的是,在广泛检查后，在63只眼中发现了特定的外周变化，涉及36（48.0％）先证者，包括周边视网膜无血管区（74.6%，47/63眼），新生血管（54.0%），荧光素渗漏（31.7%），外周色素变化（31.7%），和其他人。外显子组测序在75个先证者中的20个（26.7％）中鉴定出13个基因的21个潜在致病变体，包括Stickler综合征的基因（COL11A1和COL2A1;6/20），FEVR（FZD4、LRP5和TSPAN12；5/20），和其他(FBN1、GPR179、ZEB2、PAX6、GPR143、OPN1LW、FRMD7和CACNA1F；9/20）。对于20位先证者的周边视网膜变化，Stickler综合征相关基因的变异主要与视网膜色素变化相关，晶格退化，和视网膜无血管区域，而与FEVR相关的基因变异主要与无血管区相关，新生血管形成,和荧光素泄漏。
结论：在约四分之一的单纯性uHM患者中发现了遗传缺陷，其中在经典近视眼底下可能隐藏了多达一半的明显后果。据我们所知,这是迄今为止对单纯形uHM的第一个系统的遗传研究。除了斜视和弱视的常规护理，uHM患者需要对周边视网膜进行仔细检查和基因筛查,以确定视网膜脱离和其他并发症的风险迹象,并提供有意义的遗传咨询.
