BackgroundThe 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.MethodsA 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.ResultsWe 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.ConclusionsEast Asian-specific variants in causative genes were the major causes of RP in the Japanese population.

PURPOSE. A posterior staphyloma has been reported to be present in some eyes with retinitis pigmentosa (RP), and the purpose of this study was to determine the macular curvature of non-highly myopic RP eyes. METHODS. This was a retrospective, observational study. The medical charts of the right eyes of 143 patients with RP and 60 controls whose axial length ranged from 21.5 mm to 26.0 mm were reviewed. The mean curvature of Bruch's membrane within 6 mm of the central macula obtained from the horizontal optical coherence tomographic images were evaluated as the mean macular curvature index (MMCI). The relationships between the MMCI and other clinical factors were assessed. RESULTS. The mean MMCI of RP patients (À13.73 6 9.63 3 10 À5 lm À1) was significantly lower than that of the controls (À6.63 6 5.63 3 10 À5 lm À1). This indicated a deeper concave shape of the macula in RP eyes (P < 0.001). The MMCI was significantly correlated with the age (r ¼ 0.20; P ¼ 0.016) and the axial length (r ¼ À0.24; P ¼ 0.004). Further analysis suggested a nonlinear effect of the ellipsoid zone width on the macular curvature in the RP eyes. CONCLUSIONS. There is a high incidence of steeper macular curvatures even in non-highly myopic RP eyes, and the steepness was also affected by the degree of photoreceptor degeneration.

No abstract

Purpose To investigate clinical characteristics of RDH5 -related fundus albipunctatus (FAP) in a Japanese cohort. Methods Twenty-five patients from 22 pedigrees with RDH5 -related FAP were studied. Ophthalmic medical records were reviewed. For genetic analysis, either Sanger sequencing of the RDH5 gene or whole-exome sequencing was performed. Results Genetic analysis identified eight different RDH5 variants, including seven known RDH5 variants (p.G35S, p.G107R, p.R167H, p.A240GfsX19, p.R278X, p.R280H, and p.L310delinsEV) and a novel variant: c.259C>T (p.Q87X). The most frequently observed variant was p.L310delinsEV (65.2%, 30/46 alleles). Of 50 eyes examined, 44 eyes (88.0%) showed logMAR best-corrected visual acuity (BCVA) of 0.10 or better. In optical coherence tomography, macular involvement was observed in 12 patients (24 eyes). Ten patients (83.3%) who had good BCVA (0.10 or better) exhibited diffuse disruption of the outer retina with foveal sparing, and two patients (16.7%) exhibited diffuse disruption throughout the macula and decreased BCVA. Among the 24 eyes, ring-or crescent-shaped hyperautofluorescence or irregular autofluorescence around the fovea was observed in 15 eyes (83.3%) of 18 eyes examined by fundus autofluorescence imaging. Full-field electroretinography showed extinguished or severely decreased rod responses in all 23 examined patients, whereas decreased cone responses were seen in 17 patients (73.9%). Conclusions Multimodal imaging and electroretinography of RDH5 -related FAP revealed high frequencies of macular involvement in older patients and decreased cone responses. Our findings suggest that progressive macular/cone dysfunction, as well as delayed rod function, may be key phenotypic features of RDH5 -related FAP.

In contrast to previous reports, the thickness of the OS reflected the retinal sensitivity better than the product of OS and ONL.

Variants in the retinitis pigmentosa GTPase regulator (RPGR) gene are a major cause of X-linked inherited retinal disorder (IRD). We herein describe the clinical and genetic features of 14 patients from 13 Japanese families harboring RPGR variants in a nationwide cohort. Comprehensive ophthalmological examinations were performed to classify the patients into one of the phenotype subgroups: retinitis pigmentosa (RP) and cone rod dystrophy (CORD). The mean age of onset/at examination was 13.8/38.1 years (range, 0–50/11–72), respectively. The mean visual acuity in the right/left eye was 0.43/0.43 (range, 0.1–1.7/−0.08–1.52) LogMAR unit. Eight patients had RP, and six had CORD. Whole-exome sequencing with target analyses identified 13 RPGR variants in 730 families with IRD, including 8 novel variants. An association between the phenotype subgroup and the position of variants (cutoff of amino acid 950) was revealed. To conclude, the clinical and genetic spectrum of RPGR-associated retinal disorder was first illustrated in a Japanese population, with a high proportion of novel variants. These results suggest the distinct genetic background of RPGR in the Japanese population, in which the genotype–phenotype association was affirmed. This evidence should be helpful monitoring and counseling patients and in selecting patients for future therapeutic trials.

PURPOSE. To determine the relationship between the macular curvature and the causative genes of retinitis pigmentosa (RP). METHODS. We examined the medical records of the right eyes of 65 cases with RP (31 men and 34 women; average age, 47.6 years). There were 31 cases with the EYS variants, 11 cases with the USH2A variants, six cases with the RPGR variants, 13 cases with the RP1 variants, and four cases with the RP1L1 variants. The mean curvature of Bruch's membrane was calculated within 6 mm of the fovea as the mean macular curvature index (MMCI, 1/μm). We used multiple linear regression analysis to determine the independence of the causative genes contributing to the MMCIs after adjustments for age, sex, axial length, and width of the ellipsoid zone. RESULTS. The median MMCI was −31.2 × 10 −5 /μm for the RPGR eyes, −16.5 × 10 −5 /μm for the RP1L1 eyes, −13.0 × 10 −5 /μm for the RP1 eyes, −9.8 × 10 −5 /μm for the EYS eyes, and −9.0 × 10 −5 /μm for the USH2A eyes. Compared with the EYS gene as the reference gene, the RPGR gene was significantly related to the MMCI values after adjusting for the other parameters (P = 5.30 × 10 −6). In contrast, the effects of the other genes, USH2A, RP1, and RP1L1, were not significantly different from that of the EYS gene (P = 0.26, P = 0.49, and P = 0.92, respectively). CONCLUSIONS. The RPGR gene had a stronger effect on the steep macular curvature than the other ciliopathy-related genes.

No abstract