August 15, 2025
By Ashley Tucker, OD, FAAO, FSLS, ABO Diplomate
Photo Credit: Getty Images
This retrospective clinical study explored how both clinical and genetic factors influence the effectiveness of orthokeratology lenses in controlling myopia in children. The authors analyzed 545 myopic children (ages 8–12) who wore OrthoK lenses for one year, measuring axial length (AL) growth as the main indicator of myopia control. They also performed whole-genome sequencing (WGS) on 60 children—30 with slow AL growth (≤0.09 mm/year) and 30 with rapid growth (≥0.33 mm/year)—to examine genetic influences, focusing on 289 retinal disease-related genes from the RetNet database.
Key Clinical Findings
Older age, greater baseline AL, and more myopic baseline spherical equivalent (SE) were associated with better OrthoK control of myopia progression. Logistic regression confirmed baseline AL as a significant predictor of OrthoK effectiveness (OR = 2.83). These results align with previous studies suggesting that older children and those with higher myopia often exhibit slower AL elongation when using OrthoK.
Genetic Findings
Gene-set burden testing showed that children with more nonsynonymous variants in RetNet genes tended to have better myopia control with OrthoK. Two genes were highlighted:
- RIMS2: Associated with poorer control; highly expressed in retinal rod cells and involved in synaptic transmission at photoreceptor ribbon synapses. Mutations may impair retinal contrast sensitivity, potentially weakening the eye’s defocus-driven growth regulation.
- LCA5: Associated with better control; also expressed in rod cells and linked to retinal structure/function. Mutations can cause Leber congenital amaurosis but may also alter retinal signaling in ways that enhance OrthoK’s effect.
At the single-variant level, 16 significant SNPs were identified in RetNet genes. Two intronic variants stood out:
- rs36006402 (SLC7A14): Homozygotes had significantly lower AL growth; SLC7A14 is important in retinal development and visual function.
- rs2285814 (CLUAP1): Both homozygotes and heterozygotes had higher AL growth; CLUAP1 is linked to photoreceptor maintenance via intraflagellar transport.
Interpretation
These findings suggest that OrthoK efficacy varies due to both ocular characteristics and genetic factors influencing retinal structure and signaling. OrthoK lenses work partly by creating peripheral myopic defocus, which slows eye growth. Variations in retinal genes may modify how the retina detects and responds to these defocus cues, thereby influencing treatment outcomes.
Limitations
The genetic analysis was limited by small sample size (30 per group) and a one-year follow-up, which may not capture long-term effects. The retrospective design also meant some data loss during participant recall. Larger, prospective studies with longer follow-up are needed.
Conclusions
OrthoK lens effectiveness is influenced by baseline AL, SE, age, and genetic variation in retinal function genes. Nonsynonymous variants in retinal disease-related genes, particularly RIMS2 and LCA5, appear to modulate treatment response. The study is the first to link specific genetic factors to OrthoK efficacy, laying the groundwork for personalized myopia control strategies, including potential genetic counseling for families considering OrthoK therapy.
ABSTRACT
Ruijing Xia, Xiangyi Yu, Hao Wu, Lulu Peng, Zhenlin Du, Xiaoguang Yu, Shilai Xing, Fan Lu, Xinjie Mao
Background
This study investigated how clinical and genetic factors impact the effectiveness of orthokeratology lenses in myopia.
Methods
A retrospective clinical study was conducted with a sample of 545 children aged 8–12 years who had myopia and have initially worn orthokeratology lenses for one year. Whole-genome sequencing (WGS) was also performed on 60 participants in two groups, one with rapid axial length (AL) progression of larger than 0.33 mm and the other with slow AL progression of less than 0.09 mm. The RetNet database was used to screen candidate genes that may contribute to the effectiveness of orthokeratology lenses in controlling myopia.
Results
Children with greater baseline AL, greater spherical equivalent (SE) and greater age had better myopia control with orthokeratology lenses. A significant excess of nonsynonymous variants was observed among those with slow myopia progression, and these were prominently enriched in retinal disease-related genes. Subsequently, RIMS2 [odds ratio (OR) = 0.01, P = 0.0097] and LCA5 (OR = 9.27, P = 0.0089) were found to harbor an excess number of nonsynonymous variants in patients with slow progression of high myopia. Two intronic common variants rs36006402 in SLC7A14 and rs2285814 in CLUAP1 were strongly associated with AL growth. The identification of these novel genes associated with the effectiveness of orthokeratology lens therapy in myopic children provides insight into the genetic mechanism of orthokeratology treatment.
Conclusion
The effectiveness of orthokeratology lens treatment relates to interindividual variability in the control of AL growth in myopic eyes. The efficacy increased when patients carried more nonsynonymous variants in retinal disease-related gene sets. These data serve as reference for genetic counselling and the management of patients who choose orthokeratology lenses to control myopia.
DOI: https://doi.org/10.1186/s40662-025-00426-4
