Li Xiaoxia, Wang Siyu, Wang Yuhan, Chen Ruru, Mao Xinjie, Mei Ying, Xu Meiping, Hu Lan, Qin Chuan, Xing Shilai, Yu Xiaoguang, Qiao Liya
Department of Ophthalmology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
Institute of PSI Genomics Co., Ltd., Shanghai, China.
Invest Ophthalmol Vis Sci. 2025 Apr 1;66(4):30. doi: 10.1167/iovs.66.4.30.
Variants in the GLRA2 gene have been linked to early-onset and nonsyndromic high myopia with a X-linked inheritance. This study aimed to elucidate clinical and genetic characteristics of GLRA2-associated early-onset high myopia (eoHM).
Variants in 17 genes reported to contribute to eoHM, including GLRA2, were evaluated for pathogenic level based on in silico prediction, associated phenotypes, and cosegregation analysis. The available clinical data of individuals were summarized. Minigene constructs were generated to assess the effects of the variant c.494+1G>A in GLRA2 on splicing. We integrated previous evidence to curate the clinical validity of GLRA2 and eoHM using the ClinGen framework.
Pathogenic and likely pathogenic variants in 7 of 17 genes were identified in 47 of 389 probands with eoHM, including 21 in OPN1LW, 12 in ARR3, and 9 in GLRA2. For GLRA2, 15 pathogenic variants (10 missense and 5 truncation) were identified in 16 families, in whom probands had eoHM by X-linked inheritance. The average refraction was -9.76 diopters (D) (standard deviation: ±5.45 D). Central corneal thickness averaged 539.41 and 544.06 µm in the right and left eyes, respectively, with no or mild myopic retinal changes observed in 64.3% (27/42) of eyes. Posterior staphyloma was detected in 17 of 33 eyes (51.5%), with 6 eyes progressing to macular splitting. Most cases showed normal retinal sensitivity and stable fixation. Based on genetic and experimental evidence, the GLRA2-eoHM relationship was classified as "strong."
This research expanded the mutational spectrum of GLRA2 and reveals GLRA2 as the third most frequently implicated gene for Mendelian eoHM. Truncations and highly scored missense variants in GLRA2 are pathogenic. Myopia due to GLRA2 mutations is transmitted in X-linked inheritance, manifests with mild cone impairment, and progresses to pathologic myopia.
GLRA2基因变异与X连锁遗传的早发性非综合征性高度近视有关。本研究旨在阐明GLRA2相关早发性高度近视（eoHM）的临床和遗传特征。
根据计算机预测、相关表型和共分离分析，对17个据报道与eoHM相关的基因变异进行致病水平评估。总结个体的可用临床数据。构建小基因载体以评估GLRA2基因中c.494+1G>A变异对剪接的影响。我们整合先前的证据，使用ClinGen框架评估GLRA2与eoHM的临床有效性。
在389例eoHM先证者中的47例中鉴定出17个基因中的7个致病和可能致病变异，其中OPN1LW中有21个，ARR3中有12个，GLRA2中有9个。对于GLRA2，在16个家族中鉴定出15个致病变异（10个错义变异和5个截短变异），先证者通过X连锁遗传患有eoHM。平均屈光度为-9.76D（标准差：±5.45D）。右眼和左眼中央角膜厚度分别平均为539.41和544.06μm，64.3%（27/42）的眼睛未观察到或仅有轻度近视性视网膜改变。33只眼中有17只（51.5%）检测到后巩膜葡萄肿，其中6只眼进展为黄斑劈裂。大多数病例显示视网膜敏感度正常且注视稳定。基于遗传和实验证据，GLRA2与eoHM的关系被归类为“强”。
本研究扩展了GLRA2的突变谱，揭示GLRA2是孟德尔式eoHM中第三大最常涉及的基因。GLRA2中的截短变异和高分错义变异具有致病性。由GLRA2突变引起的近视以X连锁遗传方式传递，表现为轻度视锥细胞损害，并进展为病理性近视。
