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.

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.

Novel mutations in the RS1 gene in Japanese patients with X-linked congenital retinoschisis.

X-linked congenital retinoschisis (XLRS) is an inherited retinal disorder characterized by reduced central vision and schisis of the macula and peripheral retina. XLRS is caused by mutations in the RS1 gene. We have identified 37 different mutations in the RS1 gene, including 12 novel mutations, in 67 Japanese patients from 56 XLRS families. We present clinical features of these patients in relation to the associated mutations.

Novel MYOC gene mutation, Phe369Leu, in Japanese patients with primary open-angle glaucoma detected by denaturing high-performance liquid chromatography.

PURPOSE: To screen for mutations in the MYOC gene in Japanese patients with primary open-angle glaucoma (POAG) using denaturing high-performance liquid chromatography (DHPLC). PATIENTS AND METHODS: Blood samples were collected from 171 patients with POAG and 100 controls from seven institutions in Japan. For high-throughput analysis, seven exonic regions were amplified by polymerase chain reaction using DNA pooled from three patients; each DNA pool was then analyzed chromatographically. For analysis of a small number of samples, 7 exonic regions were amplified separately but simultaneously with annealing at 58 degrees C in each patient and then chromatographed, using 7 wells of the same 96-well plate per sample. When chromatographic patterns were abnormal by either method, the PCR products of the individual samples were sequenced. RESULTS: Four glaucoma-causing mutations were identified in five POAG patients (2.9%). One missense mutation, Phe369Leu, is new; and three others, Ile360Asn, Ala363Thr, and Thr448Pro, have been reported in Japanese patients. Phe369Leu was associated with adult onset POAG. CONCLUSIONS: Mutations in the MYOC gene were demonstrated chromatographically in 2.9% of our Japanese POAG patients. The use of pooled DNAs with DHPLC analysis is a time- and labor-saving technique. All mutations detected appear to be specific to Japanese patients.

Corneal elasticity as a measure of intra-ocular pressure: a controlled clinical examination.

PURPOSE: To determine the clinical efficacy of corneal elasticity (CE) measurements as an index of intra-ocular pressure(IOP). The considerable body of evidence linking elevated intra-ocular pressure (IOP) to glaucomatous conditions, points to the importance of the accurate and reliable measurement of IOP for diagnosis, prevention and post treatment assessments. Recently an applanation resonator sensor (ARS) for measuring IOP via CE has been proposed as an alternative to the extant Goldmann applanation tonometry (GAT). The present study examines the validity of the measure as an index of IOP in glaucomatous patients. METHODS: A structured sample of glaucomatous patients and orthogonally matched normal control subjects were assessed by the GAT and ARS methods in the research and outpatient treatment laboratory of the university Ophthalmology Department. The patient sample consisted of individuals with IOP of 16 mmHg and above and with evidence of clinically significant optic nerve damage. RESULTS: Significant correlations between GAT-IOP and ARS frequency shifts (Delta fs) for both clinical (r=.88, p<.001, n=16) and normal subjects (r=.60, p<.01, n=16) were obtained. CONCLUSIONS: The results suggest that ARS could be a clinical alternative to the extant GAT method in assessing IOP. In order to further examine the clinical efficacy of ARS-Delta fs as an accurate index of IOP, tests of a significant correlation between ARS-Delta fs and manometrically established vitreous IOP are now needed in normal and glaucomatous subjects.