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Genotype-phenotype correlations
Original research
From onset to blindness: a comprehensive analysis of RPGR-associated X-linked retinopathy in a large cohort in China
  1. Jiawen Wu1,2,3,
  2. Junfeng Li1,2,3,
  3. Daowei Zhang1,2,3,
  4. Hongli Liu1,2,3,
  5. Ting Li1,2,3,
  6. Ping Xu1,2,3,
  7. Yingke Zhao1,2,3,
  8. Chenchen Li1,2,3,
  9. Fangyuan Hu1,2,3,
  10. Qian Li1,2,3,
  11. Shenghai Zhang1,2,3,
  12. Ji-Hong Wu1,2,3
  1. 1 Department of Opthalmology, Eye and ENT Hospital, College of Medicine, Fudan University, Shanghai 200000, China
  2. 2 Shanghai Key Laboratory of Visual Impairment and Restoration, Science and Technology Commission of Shanghai Municipality, Shanghai 200000, China
  3. 3 Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, National Health Commission, Shanghai 200000, China
  1. Correspondence to Professor Ji-Hong Wu; jihongwu{at}fudan.edu.cn; Professor Shenghai Zhang; zsheent{at}163.com

Abstract

Background Variants in the RPGR are the leading cause of X-linked retinopathies (XLRPs). Further in-depth investigation is needed to understand the natural history.

Methods Review of all case records, molecular genetic testing results, best-corrected visual acuity (BCVA), retinal imaging data (including fundus autofluorescence imaging and optical coherence tomography (OCT)), static visual field (VF) assessments and full-field electroretinogram.

Results Genetic testing was conducted on 104 male patients from 89 family pedigrees, identifying 22 novel variants and 1 de novo variant. The initial symptoms appeared in 78.2% of patients at a median age of 5 years. BCVA declined at a mean rate of 0.02 (IQR, 0–0.04) logarithm of the minimum angle of resolution per year, with a gradual, non-linear decrease over the first 40 years. Autofluorescence imaging revealed macular atrophy at a median age of 36.1 (IQR, 29.9–43.2) years. Patients experienced blindness at a median age of 42.5 (IQR, 32.9–45.2) years according to WHO visual impairment categories. OCT analysis showed a mean ellipsoid zone narrowing rate of 23.3 (IQR, −1.04–22.29) µm/month, with an accelerated reduction in the first 40 years (p<0.01). The median age at which ERG no longer detected a waveform was 26.5 (IQR, 20.5–32.8) years. Comparison by variant location indicated faster progression in patients with exon 1–14 variants during the initial two decades, while those with ORF15 variants showed accelerated progression from the third decade.

Conclusions We provide a foundation for determining the treatment window and an objective basis for evaluating the therapeutic efficacy of gene therapy for XLRP.

  • Ophthalmology
  • Genetics

Data availability statement

Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/jmg-2024-110088

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    Data availability statement

    Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

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    Footnotes

    • JW and JL contributed equally.

    • Contributors J-HW and SZ are the guarantors of this study. J-HW and SZ planned the study. J-HW, SZ, JW and JL conceived and designed the study. JW, JL, D-WZ, TL, PX, YZ, CL, FH and QL recruited patients and collected data. J-HW, JW, D-WZ and HL analysed and quantified the ophthalmic imaging data. JW and JL analysed and interpreted the data. All authors read and approved the manuscript.

    • Funding We are grateful to the technical staff at the Eye and ENT Hospital of Fudan University for their assistance. This study was funded by a grant from the National Natural Science Foundation of China (NSFC) (82171055, 82271085), the National Key Research and Development Program of China (No 2020YFA0112703), the Program of Shanghai Municipal Commission of Science and Technology (21S11905900), Xuhui Hospital and regional cooperation project (23XHYD-28).

    • 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.