Reproductive Medicine Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of Obstetrics and Gynecology, Jiaxing Maternity and Child Health Care Hospital, College of Medicine, Jiaxing University, Jiaxing, China.
Invest Ophthalmol Vis Sci. 2024 Mar 5;65(3):32. doi: 10.1167/iovs.65.3.32.
Variants in the ARR3 gene have been linked to early-onset high myopia (eoHM) with a unique X-linked female-limited inheritance. However, the clinical validity of this gene-disease association has not been systematically evaluated.
We identified two Chinese families with novel ARR3 splicing variants associated with eoHM. Minigene constructs were generated to assess the effects of the variants on splicing. We integrated previous evidence to curate the clinical validity of ARR3 and eoHM using the ClinGen framework.
The variants c.39+1G>A and c.100+4A>G were identified in the two families. Minigene analysis showed both variants resulted in abnormal splicing and introduction of premature termination codons. Based on genetic and experimental evidence, the ARR3-eoHM relationship was classified as "definitive."
Our study identified two novel splicing variants of the ARR3 gene linked to eoHM and confirmed their functional validity via minigene assay. This research expanded the mutational spectrum of ARR3 and confirmed the minigene assay technique as an effective tool for understanding variant effects on splicing mechanisms.
ARR3 基因中的变异与具有独特 X 连锁女性局限性遗传的早发性高度近视（eoHM）有关。然而，该基因-疾病关联的临床有效性尚未得到系统评估。
我们鉴定了两个与 eoHM 相关的具有新型 ARR3 剪接变异的中国家系。生成了 minigene 构建体以评估变异对剪接的影响。我们整合了以前的证据，使用 ClinGen 框架对 ARR3 和 eoHM 的临床有效性进行了编纂。
在两个家系中鉴定出了 c.39+1G>A 和 c.100+4A>G 两种变异。minigene 分析表明，这两种变异均导致异常剪接并引入提前终止密码子。基于遗传和实验证据，ARR3-eoHM 关系被归类为“明确”。
我们的研究鉴定了 ARR3 基因的两个与 eoHM 相关的新型剪接变异，并通过 minigene 分析证实了它们的功能有效性。该研究扩展了 ARR3 的突变谱，并证实了 minigene 分析技术是理解变异对剪接机制影响的有效工具。
