Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases

J Med Genet. 2024 Jun 20;61(7):613-620. doi: 10.1136/jmg-2023-109750.


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.

Keywords: Genetic Testing; Genetic Therapy; Ophthalmology.

MeSH terms

  • Cone-Rod Dystrophies / genetics
  • Cone-Rod Dystrophies / pathology
  • East Asian People / genetics
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Japan
  • Leber Congenital Amaurosis / genetics
  • Leber Congenital Amaurosis / pathology
  • Male
  • Mutation
  • Retinitis Pigmentosa* / genetics
  • Retinitis Pigmentosa* / pathology
  • Usher Syndromes / genetics