You are here

  • Home
  • Archive
  • Volume 61, Issue 7
  • Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases

Article Text

Article menu
Download PDFPDF
Diagnostics
Original research
Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases
  1. Kensuke Goto1,
  2. Yoshito Koyanagi1,2,
  3. Masato Akiyama2,3,
  4. Yusuke Murakami2,
  5. Masatoshi Fukushima2,
  6. Kohta Fujiwara2,
  7. Hanae Iijima4,
  8. Mitsuyo Yamaguchi4,
  9. Mikiko Endo5,
  10. Kazuki Hashimoto6,
  11. Masataka Ishizu7,
  12. Toshiaki Hirakata8,
  13. Kei Mizobuchi9,
  14. Masakazu Takayama10,
  15. Junya Ota1,
  16. Ai Fujita Sajiki1,
  17. Taro Kominami1,
  18. Hiroaki Ushida1,
  19. Kosuke Fujita1,
  20. Hiroki Kaneko1,
  21. Shinji Ueno1,11,
  22. Takaaki Hayashi9,
  23. Chikashi Terao12,
  24. Yoshihiro Hotta10,
  25. Akira Murakami8,
  26. Kazuki Kuniyoshi13,
  27. Shunji Kusaka13,
  28. Yuko Wada14,
  29. Toshiaki Abe15,
  30. Toru Nakazawa6,
  31. Yasuhiro Ikeda7,
  32. Yukihide Momozawa4,
  33. Koh-Hei Sonoda2,
  34. Koji M Nishiguchi1
  1. 1 Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan
  2. 2 Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  3. 3 Department of Ocular Pathology and Imaging Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
  4. 4 Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
  5. 5 RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
  6. 6 Department of Ophthalmology, Tohoku University Graduate School of Medicine, Sendai, Japan
  7. 7 Department of Ophthalmology, University of Miyazaki Faculty of Medicine, Miyazaki, Japan
  8. 8 Department of Ophthalmology, Juntendo University Graduate School of Medicine, Tokyo, Japan
  9. 9 Department of Ophthalmology, The Jikei University School of Medicine, Tokyo, Japan
  10. 10 Department of Ophthalmology, Hamamatsu University School of Medicine, Hamamatsu, Japan
  11. 11 Department of Ophthalmology, Hirosaki University Graduate School of Medicine, Hisoraki, Japan
  12. 12 Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan
  13. 13 Department of Ophthalmology, Kindai University Faculty of Medicine, Osaka-sayama, Japan
  14. 14 Yuko Wada Eye Clinic, Sendai, Japan
  15. 15 Division of Clinical Cell Therapy, Tohoku University Graduate School of Medicine United Centers for Advanced Research and Translational Medicine, Sendai, Japan
  1. Correspondence to Dr Koji M Nishiguchi, Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, 466-8560, Japan; kmn{at}med.nagoya-u.ac.jp; Professor Koh-Hei Sonoda, Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan; k.sonoda.a74{at}m.kyushu-u.ac.jp

Abstract

Background As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP–allied diseases.

Methods We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines.

Results A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases.

Conclusion A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.

  • Ophthalmology
  • Genetic Testing
  • Genetic Therapy

Data availability statement

Data are available in a public, open access repository. We have uploaded variants reported in this study in ClinVar.

https://doi.org/10.1136/jmg-2023-109750

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Data availability statement

    Data are available in a public, open access repository. We have uploaded variants reported in this study in ClinVar.

    View Full Text

    Footnotes

    • KG and YK contributed equally.

    • Contributors KH, MI, THi, KM, MT, JO, AFS, TK, HU, HK, SU, THa, YH, AM, KK, SK, YW, TA, TN, YI, K-HS and KMN collected the samples and clinical data. KG, YK, HI, MY, ME, KFujit, CT and YMo performed the experiments and analysed the data. KG, YK, MA, YMo, K-HS and KMN contributed to the manuscript preparation and editing. All authors contributed to study conception and design and data interpretation, and approved the final manuscript.

    • Funding The study was supported by the Japan Retinitis Pigmentosa Registry Project and grants from Japan Agency for Medical Research and Development (23ek0109632 to YI, 23ym0126071h0002 and 23ek0109660h0001 to KMN), Japan Society for the Promotion of Science (20K23005 and 22K16969 to YK, 22K20958 to AFS, 22K09831 to SU, 21K09756 to THa, 22K09825 to KK and 23H03059 to KMN), Japanese Retinitis Pigmentosa Society (JRPS) Research Grant to YK, Nagoya University Hospital Funding for Clinical Research to KMN and Takayanagi Retina Research Award to YK.

    • Map disclaimer The depiction of boundaries on this map does not imply the expression of any opinion whatsoever on the part of BMJ (or any member of its group) concerning the legal status of any country, territory, jurisdiction or area or of its authorities. This map is provided without any warranty of any kind, either express or implied.

    • Competing interests KMN reports grants from JCR Pharmaceuticals Co, Sysmex and Novartis Pharma Co; consulting fees from Sysmex and Novartis Pharma Co; and lecture fees from Sysmex, Novartis Pharma Co and Janssen Co. KMN has patents related to gene therapy for retinitis pigmentosa. In addition, KMN is an advisory board member of Sysmex and Novartis Pharma Co.

    • 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.