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Clinical features of patients with mutations in genes for nanophthalmos
  1. Xueqing Li1,
  2. Hui Xiao1,
  3. Yihua Su2,
  4. Xueshan Xiao1,
  5. Shiqiang Li1,
  6. Shufen Lin1,
  7. Lei Fang1,
  8. Wenmin Sun1,
  9. Panfeng Wang1,
  10. James Fielding Hejtmancik3,
  11. Minbin Yu1,
  12. Liming Chen1,
  13. Qingjiong Zhang1,
  14. Xing Liu1
  1. 1Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China
  2. 2Ophthalmology Department, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  3. 3Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
  1. Correspondence to Professor Xing Liu, Sun Yat-sen University Zhongshan Ophthalmic Center, Guangzhou, China; drliuxing{at}; Professor Qingjiong Zhang; zhangqji{at}


Background/Aims To distinguish the clinical feature of nanophthalmos (NNO) caused by mutations in protease serine 56 (PRSS56), membrane-type frizzled-related protein (MFRP), myelin regulatory factor (MYRF) and transmembrane protein 98 (TMEM98) and to evaluate the association between angle-closure glaucoma (ACG) and NNO.

Methods Variants in those four genes were identified through exome sequencing/whole genome sequencing data, and bioinformatic analysis was conducted to identify pathogenic/likely pathogenic (P/LP) variants. This observational study comprehensively summarised ophthalmological data of 67 patients with NNO from 63 families. Ocular parameters from 68 eyes without surgical treatment were subjected to further analysis.

Results Totally, 67 patients from 63 families harboured 57 P/LP variants in the four genes, including 30 in PRSS56 (47.6%), 23 in MFRP (36.5%), 5 in TMEM98 (7.9%) and 5 in MYRF (7.9%). ACG was present in 79.1% of patients. An analysis of ocular parameters from 68 eyes revealed that shorter axial length (AL), lower vitreous-to-AL ratios and severe foveal hypoplasia were associated with variants in PRSS56 and MFRP. Uveal effusion was more common in patients with PRSS56 variants, while retinitis pigmentosa was frequently observed in patients with MFRP variants. Patients with MYRF variants exhibited the thinnest retinal nerve fibre layer thickness. Patients with TMEM98 variants had an earlier average onset age of glaucoma.

Conclusion Variants in PRSS56 and MFRP are the most common genetic cause of NNO. ACG is a severe complication frequently observed in these patients. Earlier onset of ACG is observed in patients with dominant NNO, while foveal hypoplasia is more common in patients with recessive disease. Recognising these features is helpful in clinical care and genetic counselling.

  • Glaucoma
  • Macula
  • Genetics

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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  • XL and HX contributed equally.

  • Contributors Conceptualisation: XL, QZ, XL, HX, YS. Methodology: XL, HX, YS, SL. Data collection: XL, HX, YS, XX, SL, SL, LF, WS, PW, MY, LC. Formal analysis: QZ, XL, SL. Writing – original draft preparation: XL. Writing – review and editing: HX, JFH, QZ, XL. Funding acquisition: XL, QZ. XL and HX contribute equally to this article. XL (the corresponding author) and QZ responsible for the overall content as the guarantors.

  • Funding This work was supported by grants from the National Natural Science Foundation of China (Grant number: 82171056, 30971588) and the Fundamental Research Funds of the State Key Laboratory of Ophthalmology (Grant number: N/A).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.