Genetic characterization of 1210 Japanese pedigrees with inherited retinal diseases by whole-exome sequencing.

Inherited retinal diseases (IRDs) comprise a phenotypically and genetically heterogeneous group of ocular disorders that cause visual loss via progressive retinal degeneration. Here, we report the genetic characterization of 1210 IRD pedigrees enrolled through the Japan Eye Genetic Consortium and analyzed by whole exome sequencing. The most common phenotype was retinitis pigmentosa (RP, 43%), followed by macular dystrophy/cone- or cone-rod dystrophy (MD/CORD, 13%). In total, 67 causal genes were identified in 37% (448/1210) of the pedigrees. The first and second most frequently mutated genes were EYS and RP1, associated primarily with autosomal recessive (ar) RP, and RP and arMD/CORD, respectively. Examinations of variant frequency in total and by phenotype showed high accountability of a frequent EYS missense variant (c.2528G>A). In addition to the two known EYS founder mutations (c.4957dupA and c.8805C>G) of arRP, we observed a frequent RP1 variant (c.5797C>T) in patients with arMD/CORD.

CLEC3B is a novel causative gene for macular-retinal dystrophy.

PURPOSE: Macular degeneration is the leading cause of blindness worldwide. In this study, we aimed to define a new subtype of macular-retinal dystrophy and its genetic predisposition in 5 families. METHODS: Exome sequencing was performed to determine the putative disease-causing genes in patients with inherited macular disorders confirmed through comprehensive ophthalmic examinations. To validate its functional consequence, adeno-associated virus-mediated mutant gene was delivered into the murine retina, and both structural and functional tests were performed to investigate its pathological effects in vivo. RESULTS: In total, 5 multigenerational families diagnosed with autosomal dominant maculoretinopathy were found to carry a pathogenic variant in a new gene, CLEC3B, which encodes tetranectin, a plasminogen kringle-4 binding protein. Consistent with the disease phenotypes of patients, mice that received subretinal injections with the CLEC3B variant displayed multiple subretinal hyperreflective deposits, reduced retinal thickness, and decreased electroretinographic responses. Moreover, the optokinetic tracking response indicated that spatial frequency was significantly lower (P < .05), implying impaired visual function in these mice. CONCLUSION: We have presented a new subtype of macular-retinal dystrophy in 5 families as well as a new pathogenic gene, CLEC3B, providing new insights into maculoretinopathy etiology.

Efficacy of a wearable night-vision aid in patients with concentric peripheral visual field loss: a randomized, crossover trial.

PURPOSE: To investigate the efficacy of our wearable night-vision aid in patients with concentric peripheral visual field loss. STUDY DESIGN: Prospective, single blind, three-group, and three-period crossover clinical study. METHODS: The study included patients with concentric peripheral visual field loss, a best-corrected visual acuity (decimal visual acuity) of 0.1 or higher in the better eye, and the presence of a central visual field. HOYA MW10 HiKARI® (HOYA Corporation), our original wearable night-vision aid, was used as the test device with three types of camera lenses (standard-, middle-, and wide-angle lenses). Under both bright and dark conditions, the angle of the horizontal visual field was measured using each of the three lens types for each group. The baseline angle was measured when each participant wore the night-vision aid (powered off). RESULTS: The study included 21 participants. Under bright condition, the perceived horizontal visual field was significantly wider than the baseline setup when using the standard-angle lens ("the standard lens"); the middle-angle lens ("the middle lens") was significantly wider than both the baseline setup and the standard lens; and the wide-angle lens ("the wide lens") was significantly wider than the other lenses. Under dark condition, the perceived horizontal visual field was again significantly wider when using the middle lens than the baseline setup and the standard lens, and when using the wide lens, the perceived horizontal visual field was again wider than when using the other lenses. The control in the bright condition was significantly wider (p < 0.001) than when used in the dark condition, while the standard-angle lens in the dark condition was significantly wider (p = 0.05) than when used in the bright condition. In regards to the middle and wide lenses, there was no statistically significant result emerging from either of the illumination conditions. CONCLUSION: Our wearable night-vision aid with a middle-angle or wide-angle lens appears to provide wider visual field images in patients with concentric peripheral visual field loss, regardless of whether the illumination conditions are bright or dark.

Genetic and Phenotypic Landscape of PRPH2-Associated Retinal Dystrophy in Japan.

Peripherin-2 (PRPH2) is one of the causative genes of inherited retinal dystrophy. While the gene is relatively common in Caucasians, reports from Asian ethnicities are limited. In the present study, we report 40 Japanese patients from 30 families with PRPH2-associated retinal dystrophy. We identified 17 distinct pathogenic or likely pathogenic variants using next-generation sequencing. Variants p.R142W and p.V200E were relatively common in the cohort. The age of onset was generally in the 40's; however, some patients had earlier onset (age: 5 years). Visual acuity of the patients ranged from hand motion to 1.5 (Snellen equivalent 20/13). The patients showed variable phenotypes such as retinitis pigmentosa, cone-rod dystrophy, and macular dystrophy. Additionally, intrafamilial phenotypic variability was observed. Choroidal neovascularization was observed in three eyes of two patients with retinitis pigmentosa. The results demonstrate the genotypic and phenotypic variations of the disease in the Asian cohort.

Base Curve of Progressive Addition Lenses Influences Clear Vision and Stereopsis Area.

PURPOSE: Progressive addition lenses (PAL) are effective, particularly for middle-aged and elderly people who require reading spectacles. However, with PALs, peripheral vision may be distorted and blurred because of both the lateral bending of the surface and the effect of unequal bending of the light coming from an off-axis location in the tangential and sagittal directions, which may lead to a decrease in the quality of vision. Till date, no evaluation of PALs has been reported with regard to peripheral and binocular vision. We investigated the influence of high-base-curve PAL on the visual function of binocular vision using a synoptophore. METHODS: The subjects were seven males and 13 females aged 50-79 years with a best-corrected visual acuity of decimal visual acuity (1.0) or higher in both eyes and addition power of 1.50-2.50 diopters as the inclusion criteria. The study design was a two-group, two-period crossover trial. Using a synoptophore, the subjective clear vision area of monocular vision and stereopsis area of binocular vision were measured while wearing conventional-base curve PAL (4-curve) and high-base-curve PAL (8-curve). HOYALUX RF SPORT 1.6 lenses (HOYA Corporation, Tokyo, Japan) were used for the test PALs. RESULTS: The clear vision area of monocular vision was significantly wider when wearing the 8-curve PAL on the temporal side of the right eye (P = 0.02), and on the temporal side of the left eye (P = 0.01). The stereopsis area of binocular vision was significantly wider in all directions when wearing the 8-curve PAL: right (P = 0.02); left (P = 0.03); right 15° upward (P = 0.02); and left 15° upward (P = 0.02). CONCLUSION: It was clarified that, compared to 4-curve PAL, clear vision and stereopsis areas are wider when wearing 8-curve PAL.

Correction to: Clinical and genetic characteristics of 14 patients from 13 Japanese families with RPGR-associated retinal disorder: report of eight novel variants.

[This corrects the article DOI: 10.1038/s41439-019-0065-7.].

Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency.

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/disease-associated 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%, respectively. These results expand the phenotypic and genotypic spectrum of EYS-RD, accounting for a high proportion of EYS-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of EYS variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders.

Clinical and genetic characteristics of 14 patients from 13 Japanese families with RPGR-associated retinal disorder: report of eight novel variants.

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.

Modified muscle transposition procedure for a case of inferior rectus muscle aplasia.

PURPOSE: We report a case of inferior rectus muscle aplasia in a 65-year-old woman. METHODS: Images were obtained using ocular motility photography and magnetic resonance imaging (MRI), and operative findings were analyzed. RESULTS: A 65-year-old woman presented with marked right hypertropia. The right eye also had microcornea, iris coloboma, and completely restricted downward movement. MRI showed absence of the inferior rectus muscle in both eyes. During surgery, it was confirmed that the right inferior rectus muscle was absent. The patient underwent a muscle transposition procedure without tenotomy or muscle splitting. A superior rectus muscle tenotomy was also performed. Postoperatively, the right eye showed hypotropia and improved downward movement. CONCLUSION: Muscle transposition without tenotomy or tendon splitting is a surgical option for the unusual abnormality presented in this paper.