The spectrum of the morphologic phenotypes and pathogenic RP1L1 variants was documented in a well-characterized Japanese cohort with OMD. A unique motif including six amino acids (1196-1201) downstream of the doublecortin domain could be a hot spot for RP1L1 pathogenic variants. The significant association of the morphologic phenotypes and genotypes indicates that there are two types of pathophysiology underlying the occult macular dysfunction syndrome: a hereditary OMD with the classical phenotype (Miyake's disease), and a nonhereditary OMD-like syndrome with progressive occult maculopathy.

Inherited retinal disorder (IRD) is a leading cause of blindness, and CRX is one of a number of genes reported to harbour autosomal dominant (AD) and recessive (AR) causative variants. Eighteen patients from 13 families with CRX-associated retinal disorder (CRX-RD) were identified from 730 Japanese families with IRD. Ophthalmological examinations and phenotype subgroup classification were performed. The median age of onset/latest examination was 45.0/62.5 years (range, 15-77/25-94). The median visual acuity in the right/left eye was 0.52/0.40 (range, −0.08-2.00/−0.18-1.70) logarithm of the minimum angle of resolution (LogMAR) units. There was one family with macular dystrophy, nine with cone-rod dystrophy (CORD), and three with retinitis pigmentosa. In silico analysis of CRX variants was conducted for genotype subgroup classification based on inheritance and the presence of truncating variants. Eight pathogenic CRX variants were identified, including three novel heterozygous variants (p.R43H, p.P145Lfs*42, and p.P197Afs*22). A trend of a genotype-phenotype association was revealed between the phenotype and genotype subgroups. A considerably high proportion of CRX-RD

Yoshitake 19 , Takeshi iwata 19 , Kazushige tsunoda 1 & JeGc study group † Biallelic variants in the EYS gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic EYS variants, to determine the clinical/genetic spectrum of EYS-associated retinal disease (EYS-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated EYS variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in EYS-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/diseaseassociated EYS variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%,

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.

Citation: Kameya S, Fujinami K, Ueno S, et al. Phenotypical characteristics of POC1B-associated retinopathy in Japanese cohort: cone dystrophy with normal funduscopic appearance. Invest Ophthalmol Vis Sci. 2019;60:3432-3446. https://doi.org/ 10.1167/iovs.19-26650 PURPOSE. Cone/cone-rod dystrophy is a large group of retinal disorders with both phonotypic and genetic heterogeneity. The purpose of this study was to characterize the phenotype of eight patients from seven families harboring POC1B mutations in a cohort of the Japan Eye Genetics Consortium (JEGC). METHODS.Whole-exome sequencing with targeted analyses identified homozygous or compound heterozygous mutations of the POC1B gene in 7 of 548 families in the JEGC database. Ophthalmologic examinations including the best-corrected visual acuity, perimetry, fundus photography, fundus autofluorescence imaging, optical coherence tomography, and full-field and multifocal electroretinography (ERGs) were performed.RESULTS. There were four men and four women whose median age at the onset of symptoms was 15.6 years (range, 6-23 years) and that at the time of examination was 40.3 years (range, 22-67 years). The best-corrected visual acuity ranged from À0.08 to 1.52 logMAR units. The funduscopic appearance was normal in all the cases except in one case with faint mottling in the fovea. Optical coherence tomography revealed an absence of the interdigitation zone and blurred ellipsoid zone in the posterior pole, but the foveal structures were preserved in three cases. The full-field photopic ERGs were reduced or extinguished with normal scotopic responses. The central responses of the multifocal ERGs were preserved in two cases. The diagnosis was either generalized cone dystrophy in five cases or cone dystrophy with foveal sparing in three cases.CONCLUSIONS. Generalized or peripheral cone dystrophy with normal funduscopic appearance is the representative phenotype of POC1B-associated retinopathy in our cohort.Whole-exome sequencing and targeted sequence analyses of the 301 retinal disease-associated genes (including genes of Retnet; https://sph.uth.edu/retnet/, in the public domain) were done according to the published protocol of the NISO. 35 Paired-end sequence library construction and exome capturing Downloaded from iovs.arvojournals.org on 07/08/2020 FIGURE 8. Horizontal and vertical OCT images of the left eye of patient 1 recorded at the age 35 years (A) and 39 years (B).Longitudinal reflectivity profiles at the fovea are shown below the OCT images. EZ and IZ are preserved in the fovea at the age 35 years but they are blurred at the age of 39 years. The reflectivity profiles show small peaks of IZ at the age 35 years but not at 39 years. The reflectance intensity of the IZ relative to the RPE was 0.82 at the age 35 years and 0.63 at the age 39 years. The reflectance intensity of the EZ relative to the RPE was 0.86 at the age 35 years and 0.77 at the age 39 years. The reflectivity was averaged in width as indicated by the yellow lines. ILM, internal limiting membra...

The three patients with LCA/EORD had a progressive decrease of their vision with the formation of a posterior staphyloma. This is the first report of Japanese patients with LCA/EORD with a RDH12 mutation.

DRAM2-associated retinopathy is a rare inherited retinal dystrophy, and its outcome has not been determined. A single retinal involvement by a mutation of the DRAM2 gene is unexplained. We found three unrelated patients with a disease-causing DRAM2 variant in a biallelic state from 1555 Japanese individuals of 1314 families with inherited retinal dystrophy. We reviewed their medical records and examined their peripheral lymphocytes by transmission electron microscopy (TEM). Patient 1 was a 38-year-old woman who complained of night blindness and reduced vision. She developed macular degeneration at age 43 years. Patients 2 and 3 were a man and a woman both of whom noticed night blindness in their 30s. Both had a degeneration in the macula and midperiphery in their 40s, which progressed to a diffuse retinal degeneration in their 60s when their vision was reduced to hand motions. Three novel DRAM2 variants were identified. TEM of the lymphocytes of Patients 1 and 2 showed abnormal structures in 40.6% and 0.3% of the peripheral lymphocytes, respectively. We concluded that the DRAM2-associated retinopathy of our patients was a progressive rod-cone dystrophy, and the visual outcome was poor. The systemic effect of DRAM2 mutations may be compensable and have variations.

To determine the clinical and genetic characteristics of patients with GUCY2Dassociated retinal disorder (GUCY2D-RD). Methods: Fifteen patients from 12 families with inherited retinal disorder (IRD) and harboring GUCY2D variants were ascertained from 730 Japanese families with IRD. Comprehensive ophthalmological examinations, including visual acuity (VA) measurement, retinal imaging, and electrophysiological assessment were performed to classify patients into three phenotype subgroups; macular dystrophy (MD), cone-rod dystrophy (CORD), and Leber congenital amaurosis (LCA). In silico analysis was performed for the detected variants, and the molecularly confirmed inheritance pattern was determined (autosomal dominant/recessive [AD/AR]). Results: The median age of onset/examination was 22.0/38.0 years (ranges, 0-55 and 1-73) with a median VA of 0.80/0.70 LogMAR units (ranges, 0.00-1.52 and 0.10-1.52) in the right/left eye, respectively. Macular atrophy was identified in seven patients (46.7%), and two had diffuse fundus disturbance (13.3%), and six had an essentially normal