Abstract
PURPOSE: 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). METHODS: 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. RESULTS: 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." CONCLUSIONS: 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.