Aims To elucidate genetic background of early-onset high myopia (eoHM) and characteristics of ARR3 -associated MYP26. Methods Variants in 14 genes reported to contribute to eoHM, including ARR3 , were selected from exome sequencing data set and classified into different categories following American College of Medical Genetics and Genomics guidelines based on in silico prediction, associated phenotypes, confirmation and cosegregation analysis. The available clinical data of individuals were summarised. Results Pathogenic and likely pathogenic variants in three of 14 genes were identified in 52 of 928 families with eoHM, including 29 in ARR3 , 22 in OPN1LW and 1 in LRPAP1 . For ARR3 , 24 pathogenic variants (16 truncation and 8 missense) were identified in 66 women and 12 men, in whom 64 women and 4 men had eoHM by X-linked female-limited inheritance. Refraction ranged from −5.00 to −28.75 diopter (−12.58±4.83). Mild-to-moderately reduced cone responses were recorded in 76.9% (10/13) of patients with electroretinogram recordings. Most patients (75.9%, 41/54) had mild myopic fundus changes (C0 to C1). Genotype–phenotype analysis suggested that the myopic retinopathy degree was correlated with age and the variant’s nature. Peripheral retinal degeneration was observed in 38.5% (5/13) patients using wide-field examinations. Conclusion This study reveals ARR3 as the most frequently implicated gene for Mendelian eoHM. Truncations and highly scored missense variants in ARR3 are pathogenic. Myopia due to ARR3 mutations is transmitted in X-linked female-limited inheritance, manifests with mild cone impairment and slowly progresses to pathologic myopia. Identification of the most common cause for Mendelian eoHM provides a valuable starting point into the molecular mechanism of myopia. Data are available upon reasonable request.

中文翻译：

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ARR3相关MYP26的遗传和临床状况：具有独特遗传性的孟德尔早发性高度近视的最常见原因

目的 阐明早发性高度近视 (eoHM) 的遗传背景和 ARR3 相关 MYP26 的特征。方法 从外显子组测序数据集中选择包括 ARR3 在内的 14 个据报道与 eoHM 相关的基因的变异体，并根据美国医学遗传学和基因组学学院的指南，基于计算机预测、相关表型、确认和共分离分析将其分为不同的类别。总结了个体的可用临床数据。结果 在 928 个 eoHM 家系中的 52 个家族中，鉴定出 14 个基因中的 3 个基因的致病性和可能致病性变异，其中 ARR3 中 29 个、OPN1LW 中 22 个、LRPAP1 中 1 个。对于ARR3，在66名女性和12名男性中鉴定出24种致病性变异（16种截短和8种错义），其中64名女性和4名男性通过X连锁女性有限遗传患有eoHM。屈光度范围为-5.00至-28.75屈光度(-12.58±4.83)。76.9% (10/13) 的视网膜电图记录患者的视锥细胞反应轻度至中度降低。大多数患者（75.9%，41/54）有轻度近视眼底改变（C0至C1）。基因型-表型分析表明，近视视网膜病变程度与年龄和变异性质相关。使用广视野检查发现 38.5% (5/13) 的患者出现周边视网膜变性。结论 这项研究表明 ARR3 是孟德尔 eoHM 最常涉及的基因。ARR3 中的截短和高分错义变异具有致病性。ARR3突变引起的近视在X连锁女性有限遗传中传播，表现为轻度视锥细胞损伤，并缓慢进展为病理性近视。孟德尔 eoHM 最常见原因的识别为近视的分子机制提供了一个有价值的起点。数据可根据合理要求提供。