Background The genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population.
Methods A total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases.
Results We successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658*) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases.
Conclusions East Asian-specific variants in causative genes were the major causes of RP in the Japanese population.
- retinitis pigmentosa
- genetic epidemiology
- next-generation sequencing
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Contributors YKo, MA, KMN, YKa, YIk, MKub and K-HS designed the study. YKo, KMN, MKum, YMu, KO, TA, SK, DG, TH, KK, KH, SU, YH, AM, HT, YW, TN, TI, YIk and K-HS collected the samples and clinical data. YKo, MA, KMN, YMo, ST, CI, YIw and MKub performed the experiments and analysed the data. YKo, MA, KMN, YMo, YKa, MKub and K-HS contributed to the manuscript preparation and editing. All authors contributed to study conception and design, data interpretation, and approved the final manuscript.
Funding This work was supported by Japan Agency for Medical Research and Development grants 17ek0109213h0002 (to KMN) and JP17lk1403004 (to TA), and Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant 17K111447, to YH).
Competing interests SU reports personal fees from Nidek, Chuo Sangio, Santen and Alcon outside the submitted work. AM reports grants from Pfizer Japan, Abbott Japan, Otsuka Pharmaceutical, Eisai, Alcon Japan, Novartis Pharma KK, SEED and Santen Pharmaceutical, and personal fees from Lion Japan outside the submitted work. In addition, AM has a patent hydrogel contact lens for gene treatment licensed. HT reports personal fees from Rohto Pharmaceutical, Takeda Pharmaceutical, Mitsubishi Tanabe, AbbVie, Daiichi Sankyo, Chuo Sangio, Sanofi, Nihon Tenganyaku, Alcon Pharma, Bayer and Graybug Vision, grants and personal fees from Nidek, Otsuka, Pfizer, Santen, Alcon, Novartis, Senju, Kowa and Wakamoto, grants from HOYA and Allergan Japan, and personal fees and non-financial support from Carl Zeiss Meditec outside the submitted work. In addition, HT has a patent pending with Nidek.
Patient consent for publication Not required.
Ethics approval This study was approved by the ethics committees of all the collaborating hospitals and was conducted in accordance with the tenets of the Declaration of Helsinki on biomedical research involving human subjects. Written informed consent was obtained from all subjects prior to participation in the study.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
Author note The Japanese Retinitis Pigmentosa Registry Project (https://secure2.visitors.jp/retinal_pigment/login/) will host the data from this research. At the time of publishing (June 2019), the website is under construction.