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Cited by 4Retinal Development and DisordersOphthalmology and Visual Impairment StudiesGenomics and Rare Diseases

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

Open access
Rui, Xue, Li, Huiping, Ma, Runqing, Yang, Shangying, lian, Yuanyuan, Cheng, Wanyu, Ma, Meijiao, Rong, Weining, Sheng, Xunlun·2025·Scientific Reports
DOI 10.1038/s41598-025-95574-xPMC PMC11965419

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Abstract

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.

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Figures

Fig. 1 Mutation proportions grouped by the genes reported to cause myopia or not, and mutation types. The variants with identifified in patients with early-onset high myopia, 18 genes that were previously reported to cause phenotypes including myopia,harbored mutations in 9(32%) other genes not previously reported in myopia.
Fig. 1 Mutation proportions grouped by the genes reported to cause myopia or not, and mutation types. The variants with identifified in patients with early-onset high myopia, 18 genes that were previously reported to cause phenotypes including myopia,harbored mutations in 9(32%) other genes not previously reported in myopia.CC BY-NC-ND · PubMed Central
Fig. 2 The Sanger-sequencing photograph of probands. II1 represents the proband, I1 represents the father of the proband, I2 represents the mother of the proband.In particular, II2 of F9 represents the proband, II1 is the elder brother of the proband; II2 of F11 represents the proband, II1 is the elder sister of the proband; II2 of F13 represents the younger sister of the proband; II2 of F24 represents the younger brother of the proband. The black arrow indicates the site of the mutation. The red arrow in F22 indicates a high frequency mutation, which has been filtered.
Fig. 2 The Sanger-sequencing photograph of probands. II1 represents the proband, I1 represents the father of the proband, I2 represents the mother of the proband.In particular, II2 of F9 represents the proband, II1 is the elder brother of the proband; II2 of F11 represents the proband, II1 is the elder sister of the proband; II2 of F13 represents the younger sister of the proband; II2 of F24 represents the younger brother of the proband. The black arrow indicates the site of the mutation. The red arrow in F22 indicates a high frequency mutation, which has been filtered.CC BY-NC-ND · PubMed Central
Fig. 3 The Wide-angle fundus photograph of F1,F2,F4,F10,F12,F15,F24,F25. (B,C,D,E,F,G) showed fundus tessellation; (A,F,H) showed fundus tessellation and diffuse retinal atrophy.
Fig. 3 The Wide-angle fundus photograph of F1,F2,F4,F10,F12,F15,F24,F25. (B,C,D,E,F,G) showed fundus tessellation; (A,F,H) showed fundus tessellation and diffuse retinal atrophy.CC BY-NC-ND · PubMed Central
Fig. 4 The phenotype of F23 pedigree with TSPAN12 mutation. (A) The fundus fluorescein angiography (FFA) of F23 proband: The peripheral blood vessels of both eyes were straight with decreased density, abnormal anastomosis of terminal arteries and veins, and peripheral telangiectasia with a small amount of leakage; (B) The FFA of F23 proband’s father: the vessels in both eyes did not develop to the periphery and terminated in front of the serrated edge, with a clear crest-like demarcation between the avascular area and the normal vascularized retina. The peripheral retinal vascular branches are numerous, with brush-like changes and a small amount of leakage. (C) Pedigree of affected family; (D) Sequence chromatograms of identified mutations; (E) The homology of amino acid sequences between human TSPAN12 and other species. The amino acid at position 151 is highly conserved among species. The mutated residue 151 is boxed and indicated.
Fig. 4 The phenotype of F23 pedigree with TSPAN12 mutation. (A) The fundus fluorescein angiography (FFA) of F23 proband: The peripheral blood vessels of both eyes were straight with decreased density, abnormal anastomosis of terminal arteries and veins, and peripheral telangiectasia with a small amount of leakage; (B) The FFA of F23 proband’s father: the vessels in both eyes did not develop to the periphery and terminated in front of the serrated edge, with a clear crest-like demarcation between the avascular area and the normal vascularized retina. The peripheral retinal vascular branches are numerous, with brush-like changes and a small amount of leakage. (C) Pedigree of affected family; (D) Sequence chromatograms of identified mutations; (E) The homology of amino acid sequences between human TSPAN12 and other species. The amino acid at position 151 is highly conserved among species. The mutated residue 151 is boxed and indicated.CC BY-NC-ND · PubMed Central
Fig. 5 The phenotype of F16 proband with COL2A1 autogenetic mutation. (A) Wide-angle fundus photograph showed fundus tessellation; (B) anterior segment photography showed the vitreous is typically membrane-like; (C) pedigree of affected family; (D) sequence chromatograms of identified mutations; (E) The homology of amino acid sequences between human COL2A1 and other species. The amino acid at position 940 is highly conserved among species. The mutated residue 940 is boxed and indicated.
Fig. 5 The phenotype of F16 proband with COL2A1 autogenetic mutation. (A) Wide-angle fundus photograph showed fundus tessellation; (B) anterior segment photography showed the vitreous is typically membrane-like; (C) pedigree of affected family; (D) sequence chromatograms of identified mutations; (E) The homology of amino acid sequences between human COL2A1 and other species. The amino acid at position 940 is highly conserved among species. The mutated residue 940 is boxed and indicated.CC BY-NC-ND · PubMed Central
Fig. 6 Cluster I (red node) is involved in the transduction of visual signals , retinal feedback machanism ;Cluster II (yellow node) is involved in extracellular matrix (ECM) formation; Cluster III blue node) is involved in Wnt signaling pathway; Cluster IV (green node) is involved in energy metabolism;Cluster V (purple node is involved in lens development and protein stability.
Fig. 6 Cluster I (red node) is involved in the transduction of visual signals , retinal feedback machanism ;Cluster II (yellow node) is involved in extracellular matrix (ECM) formation; Cluster III blue node) is involved in Wnt signaling pathway; Cluster IV (green node) is involved in energy metabolism;Cluster V (purple node is involved in lens development and protein stability.CC BY-NC-ND · PubMed Central
Fig. 7 (A) The green structure represents ZNF644, and the blue structure represents P4HA2. The docking results suggest a stable interaction between these two proteins, where ZNF644 and P4HA2 are positioned in a manner that facilitates their interaction. (B) The docking result between ZNF644 (green) and ARR3 (blue) shows a distinct pattern of interaction. ZNF644 appears to interact with ARR3, which is a key protein involved in visual signaling. This docking model suggests a potential functional interaction between the two proteins in the visual system.
Fig. 7 (A) The green structure represents ZNF644, and the blue structure represents P4HA2. The docking results suggest a stable interaction between these two proteins, where ZNF644 and P4HA2 are positioned in a manner that facilitates their interaction. (B) The docking result between ZNF644 (green) and ARR3 (blue) shows a distinct pattern of interaction. ZNF644 appears to interact with ARR3, which is a key protein involved in visual signaling. This docking model suggests a potential functional interaction between the two proteins in the visual system.CC BY-NC-ND · PubMed Central

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Research works printed but not linked: 1

  1. Rui, X. et al. Genotypes and phentypes of hereditary eye diseases associated with early-onset high myopia. Chin J Exp Ohthalmol 41(7), 662–674. https://doi.org/10.3760/cma.j.cn115989-20211216-00695 (2023). · DOI

Metadata

Authors
Rui, X., Li, H., Ma, R., Yang, S., lian, Y., Cheng, W., Ma, M., Rong, W., & Sheng, X.
Affiliations
  • Aier Eye Hospital Group (China) (CN)
  • Ningxia Hui Autonomous Region Peoples Hospital (CN)
Corresponding author
  • Rong, Weining
  • Sheng, Xunlun
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2025-04-02
Volume
15
Issue
1
Pages
11252-11252
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-025-95574-x
PMC
PMC11965419
OpenAlex
W4409148677
Cited by
4
References
44
Citations by year
2026: 3 · 2025: 1
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (82260206)
  • the key research and development project of Ningxia Hui Autonomous Region (2024BEG02017)
  • the training project of the scientific innovation commanding talented person in Ningxia Hui Autonomous Region (2020GKLRLX13)
  • Major achievement transformation project of Ningxia Hui Autonomous Region (2022CJE09011)
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Development and Disorders
  • Health Sciences › Medicine › Ophthalmology › Ophthalmology and Visual Impairment Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
candidate genes, pathogenic variants, inherited retinal disease, Stickler syndrome, protein-protein interaction network, hub genes, COL5A1, COL2A1, COL11A1, novel variants, Chinese family, genetic screening, protein-protein docking, alphaB-crystallin
MeSH terms
Exome Sequencing, East Asian People, Adolescent, Child, Child, Preschool, China, Female, Humans, Male, Myopia, Pedigree, Age of Onset, Genetic Predisposition to Disease, Asian People, Protein Interaction Maps

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Rui, X., Li, H., Ma, R., Yang, S., lian, Y., Cheng, W., Ma, M., Rong, W., & Sheng, X. (2025). Whole-exome sequencing screening for candidate genes and potential pathogenic variants associated with early-onset high myopia in 47 Chinese families. Scientific Reports. https://doi.org/10.1038/s41598-025-95574-x

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