Whole-exome sequencing screening for candidate genes and potential pathogenic variants associated with early-onset high myopia in 47 Chinese families

Early-onset high myopia (eoHM) occurs before school age and is an ideal model for monogenic studies of high myopia due to minimal environmental influence. This study screened for genes and variants associated with eoHM in 47 unrelated Chinese patients with eoHM. Protein-protein interaction (PPI) network analysis was conducted to detect interactions among candidate genes, and protein-protein docking was performed. In 28 patients (28/47, 59.6%), 32 potential pathogenic variants in 22 candidate genes were identified, including 24 novel variants. Among these 28 patients, 64.3% (18/28) carried pathogenic variants in RetNet genes. Of these, 12 patients (42.9%, 12/28) had pathogenic variants in six known genes (TSPAN12, CACNA1F, USH2A, RPGR, COL2A1, and COL11A1), which are responsible for retinal dystrophy and Stickler syndrome associated with eoHM. Additionally, 7 patients (25.0%, 7/28) carried pathogenic variants in seven candidate genes for ocular disease (POLA1, TMEM231, HK1, GSN, COL5A1, CRYBB3, and WDR), which were identified as potentially pathogenic in Chinese eoHM patients for the first time. Phenotype analysis showed that 11 patients presented with only high myopia, 10 patients had inherited retinal diseases (IRDs) with eoHM, and 7 patients had ocular-only Stickler syndrome (Ocular-STL) with eoHM. The initial clinical records of these 17 patients did not show recognizable signs of other primary diseases except for high myopia, and further specific clinical examinations confirmed the diagnosis of IRDs or Stickler syndrome through eoHM. The PPI network analysis identified 87 candidate genes associated with early-onset high myopia (eoHM), grouped into four functional clusters. Thirteen hub genes, including RPGR, COL5A1, CRYAB, and FBN1, were crucial for the pathogenesis of myopia. The network showed strong biological relevance with highly significant enrichment (p-value < 1.0e-16). Our study expands the list of candidate genes associated with eoHM and suggests that eoHM may be the first reason for children to visit an ophthalmology clinic and an important clue for clinicians to detect underlying ocular diseases. These findings highlight the complex interplay of these genes, providing valuable insights into the molecular mechanisms of myopia and potential targets for future therapeutic interventions.