Identification of a novel nonsense variant in ARR3 in a family with early-onset high myopia.

BACKGROUNDS: Early-onset high myopia (EoHM) is a severe refractive error that can result in significant vision loss. A known genetic cause involves mutations in the X-linked Arrestin-3 (ARR3) gene, which typically presents with a female-limited inheritance pattern, in which asymptomatic fathers transmit the variant to their affected daughters. OBJECTIVE: This study aims to present a unique case of EoHM characterized by paternal transmission of a novel ARR3 variant and to explore potential underlying molecular mechanisms through an exploratory bioinformatic analysis. METHODS: We collected the clinical phenotypes for the family and sequenced the blood using NGS and Sanger sequencing. Bioinformatic analysis of the GSE5338 dataset revealed a potential interaction network involving ARR3, NR2E3 (a photoreceptor development regulator), and OPN1MW (a cone opsin gene). RESULTS: The proband exhibited severe EoHM with stretched axial lengths (ALs) (24.09 and 24.43 mm) and pronounced myopic astigmatism. The asymptomatic father passed on a new nonsense variation in the ARR3 gene, c.7A > T (p.K3Ter). Exploratory bioinformatic analysis of a murine retinal dataset hinted at a possible regulatory relationship, wherein overexpression of the photoreceptor transcription factor Nr2e3 might be linked to the downregulation of Arr3 and the cone opsin gene Opn1mw. CONCLUSIONS: This study reports a novel ARR3 mutation within a family affected by EoHM, expanding the known mutational spectrum of this disease and offering vital insights for genetic counseling. Furthermore, our bioinformatic analysis has generated a hypothesis that NR2E3-mediated downregulation of both ARR3 and OPN1MW may contribute to the disease phenotype, a link that warrants future investigation in human models.