Clinical and genetic characteristics of 14 patients from 13 Japanese families with RPGR-associated retinal disorder: report of eight novel variants.
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SUBMITTER: Mawatari G
PROVIDER: S-EPMC6804603 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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 in ADCORD was determined in the Japanese cohort (39.1%), often showing the mild phenotype (CORD) with late-onset disease (sixth decade). Frequently found heterozygous missense variants located within the homeodomain underlie this mild phenotype. This large cohort study delineates the disease spectrum of CRX-RD in the Japanese population.
| S-EPMC7293272 | biostudies-literature
Project description:PurposeTo determine the clinical and genetic characteristics of patients with GUCY2D-associated retinal disorder (GUCY2D-RD).MethodsFifteen 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]).ResultsThe 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 fundus (40.0%). There were 11 patients with generalized cone-rod dysfunction (78.6%), two with entire functional loss (14.3%), and one with confined macular dysfunction (7.1%). There were nine families with ADCORD, one with ARCORD, one with ADMD, and one with ARLCA. Ten GUCY2D variants were identified, including four novel variants (p.Val56GlyfsTer262, p.Met246Ile, p.Arg761Trp, p.Glu874Lys).ConclusionsThis large cohort study delineates the disease spectrum of GUCY2D-RD. Diverse clinical presentations with various severities of ADCORD and the early-onset severe phenotype of ARLCA are illustrated. A relatively lower prevalence of GUCY2D-RD for ADCORD and ARLCA in the Japanese population was revealed.Translational relevanceThe obtained data help to monitor and counsel patients, especially in East Asia, as well as to design future therapeutic approaches.
| S-EPMC7408927 | biostudies-literature
Project description:Genetic characteristics and a long-term clinical follow-up of 18 Slovenian retinitis pigmentosa GTPase regulator (RPGR) patients from 10 families with retinitis pigmentosa (RP) or cone/cone-rod dystrophy (COD/CORD) are reported. RP (eight families) was associated with two already known (p.(Ser407Ilefs*46) and p.(Glu746Argfs*23)) and five novel variants (c.1245+704_1415-2286del, p.(Glu660*), p.(Ala153Thr), c.1506+1G>T, and p.(Arg780Serfs*54)). COD (two families) was associated with p.(Ter1153Lysext*38). The median age of onset in males with RP (N = 9) was 6 years. At the first examination (median age of 32 years), the median best corrected visual acuity (BCVA) was 0.30 logMAR, and all patients had a hyperautofluorescent ring on fundus autofluorescence (FAF) encircling preserved photoreceptors. At the last follow-up (median age of 39 years), the median BCVA was 0.48 logMAR, and FAF showed ring constriction transitioning to patch in 2/9. Among females (N = 6; median age of 40 years), two had normal/near-normal FAF, one had unilateral RP (male pattern), and three had a radial and/or focal pattern of retinal degeneration. After a median of 4 years (4-21) of follow-up, 2/6 exhibited disease progression. The median age of onset in males with COD was 25 years. At first examination (median age of 35 years), the median BCVA was 1.00 logMAR, and all patients had a hyperautofluorescent FAF ring encircling foveal photoreceptor loss. At the last follow-up (median age of 42 years), the median BCVA was 1.30 logMAR, and FAF showed ring enlargement. The majority of the identified variants (75%; 6/8) had not been previously reported in other RPGR cohorts, which suggested the presence of distinct RPGR alleles in the Slovenian population.
| S-EPMC9958649 | biostudies-literature
Project description:Background: This study analyzed the phenotypes and genotypes of 41 Chinese families with inherited retinal dystrophy (IRD) and RPGR gene mutations. Methods: This retrospective analysis evaluated a cohort of 41 patients who were subjected to a specific Hereditary Eye Disease Enrichment Panel (HEDEP) analysis. All (likely) pathogenic variants were determined by Sanger sequencing, and co-segregation analyses were performed on the available family members. All cases were subjected to Sanger sequencing for RPGR open reading frame 15 (ORF15) mutations. Results: A total of 41 probands from different families with a clinical diagnosis of retinitis pigmentosa (RP; 34 cases) and cone-rod dystrophy (CORD; 7 cases) were included in this cohort. According to clinical information, 2, 18, and 21 cases were first assigned as autosomal dominant (AD), sporadic, and X-linked (XL) inheritance, respectively. Several cases of affected females who presented with a male phenotype have been described, posing challenges at diagnosis related to the apparent family history of AD. Mutations were located in RPGR exons or introns 1-14 and in ORF15 of 12 of 41 (29.3%) and 29 of 41 (70.7%) subjects, respectively. Thirty-four (likely) pathogenic mutations were identified. Frameshifts were the most frequently observed variants, followed by nonsense, splice, and missense mutations. Herein, a detailed description of four RP patients carrying RPGR intronic mutations is reported, and in vitro splice assays were performed to confirm the pathogenicity of these intronic mutations. Conclusion: Our findings provide useful insights for the genetic and clinical counseling of patients with XL IRD, which will be useful for ongoing and future gene therapy trials.
| S-EPMC9582779 | biostudies-literature
Project description:PurposeTo define genetic variants associated with variable severity of X-linked progressive retinal atrophy 1 (XLPRA1) caused by a five-nucleotide deletion in canine RPGR exon ORF15.MethodsA genome-wide association study (GWAS) was performed in XLPRA1 phenotype informative pedigree. Whole genome sequencing (WGS) was used for mutational analysis of genes within the candidate genomic region. Retinas of normal and mutant dogs were used for gene expression, gene structure, and RNA duplex analyses.ResultsGWAS followed by haplotype phasing identified an approximately 4.6 Mb candidate genomic interval on CFA31 containing seven protein-coding genes expressed in retina (ROBO1, ROBO2, RBM11, NRIP1, HSPA13, SAMSN1, and USP25). Furthermore, we identified and characterized two novel lncRNAs, ROBO1-AS and ROBO2-AS, that display overlapping gene organization with axon guidance pathway genes ROBO1 and ROBO2, respectively, producing sense-antisense gene pairs. Notably, ROBO1-AS and ROBO2-AS act in cis to form lncRNA/mRNA duplexes with ROBO1 and ROBO2, respectively, suggesting important roles for these lncRNAs in the ROBO regulatory network. A subsequent WGS identified candidate genes within the genomic region on CFA31 that might be implicated in modifying severity of XLPRA1. This approach led to discovery of genetic variants in ROBO1, ROBO1-AS, ROBO2-AS, and USP25 that are strongly associated with the XLPRA1 moderate phenotype.ConclusionsThe study provides new insights into the genetic basis of phenotypic variation in severity of RPGRorf15-associated retinal degeneration. Our findings suggest an important role for ROBO pathways in disease progression further expanding on our previously reported changes of ROBO1 expression in XLPRA1 retinas.
| S-EPMC7745631 | biostudies-literature
Project description:Previous studies have reported clinical characteristics of hoarding disorder (HD), such as early onset, a chronic course, familiality, high unmarried rate, and high rates of comorbidities. However, clinical research targeting Japanese HD patients has been very limited. As a result, there is a low recognition of HD in Japan, leading to insufficient evaluation and treatment of Japanese HD patients. The aim of the current study was to delineate the clinical characteristics of Japanese HD patients. Thirty HD patients, 20 obsessive-compulsive disorder (OCD) patients, and 21 normal controls (NC) were targeted in this study. The HD group had a tendency toward higher familiality, earlier onset, and longer disease duration compared to the OCD group. In addition, the HD group showed a significantly higher unmarried rate than the NC group. The top two comorbidities in the HD group were major depressive disorder (56.7%) and attention-deficit/hyperactivity disorder (26.7%). The HD group had significantly higher scores on hoarding rating scales and lower scores on the Global Assessment of Functioning Scale than the other two groups. The current study showed a clinical trend in Japanese HD patients similar to previous studies in various countries, suggesting that HD may be a universal disease with consistent clinical symptoms.
| S-EPMC7063155 | biostudies-literature
Project description:X-linked retinitis pigmentosa (XLRP), a rare form of retinitis pigmentosa (RP), is predominantly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. Affected males often present with severe phenotypes and early disease onset. In contrast, female carriers are usually asymptomatic or show stationary phenotypes. Herein, we reported an 8-year-old female carrier, a daughter of a confirmed RP father with RPGR mutation, with an early onset of progressive cone-rod pattern retinal dystrophy. Additionally, the carrier experienced visual snow-like symptom as long as she recalled. Ophthalmological examination showed the reduction of visual acuity and attenuation of photoreceptor functions since the age of 5 years. Further analysis revealed a heterozygous pathogenic variant of the RPGR gene and a random X-inactivation pattern. Although she harboured an identical RPGR variant as the father, there were phenotypic intrafamilial variations. The information on the variety of genotypic and phenotypic presentations in XLRP carriers is essential for further diagnosis, management, and monitoring of these cases, including the design of future gene therapy trials.
| S-EPMC8517444 | biostudies-literature
Project description:ObjectiveTo compare baseline characteristics and treatment response of participants with hemiretinal vein occlusion (HRVO) with those of participants with branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) in the Standard Care vs COrticosteroid for REtinal Vein Occlusion (SCORE) Study.MethodsEyes were randomized to standard care, 1 mg intravitreal triamcinolone acetonide, or 4 mg intravitreal triamcinolone acetonide. Standard care was observation in the SCORE-CRVO trial and grid photocoagulation in the SCORE-BRVO trial. The HRVO eyes were enrolled in the SCORE-BRVO trial. Baseline characteristics, changes in visual acuity and center point thickness, safety outcomes, and number of treatments were compared among HRVO, BRVO, and CRVO participants.ResultsAt baseline, HRVO eyes were intermediate between BRVO and CRVO eyes in area of retinal thickening, area of fluorescein leakage, visual acuity, and center point thickness. No differences in visual acuity change from baseline to 1 year were noted between standard care groups for HRVO and BRVO. Within triamcinolone-treated eyes, HRVO eyes did not differ from BRVO eyes in visual acuity change, but HRVO eyes fared better than CRVO eyes. There were no differences in center point thickness change between standard care groups for HRVO and BRVO, nor were there differences across the 3 disease entities for triamcinolone-treated eyes. There were no differences in frequency of protocol treatments and adverse events.ConclusionsThe HRVO participants were similar to BRVO and CRVO participants regarding most demographic characteristics, with fundus findings intermediate between BRVO and CRVO. In the SCORE Study, HRVO was treated as BRVO; HRVO eyes responded to treatment similarly to BRVO eyes, and there was no difference among the 3 disease entities in frequency of protocol treatments and adverse events.Trial registrationclinicaltrials.gov Identifier: NCT00105027.
| S-EPMC6640132 | biostudies-literature
Project description:PurposeTo evaluate the association between ellipsoid zone (EZ) on spectral domain optical coherence tomography (SD-OCT) and visual acuity letter score (VALS) in participants with retinal vein occlusion in the Study of Comparative Treatments for Retinal Vein Occlusion 2.MethodsSD-OCT scans of 362 participants were qualitatively assessed at baseline and months 1, 6, 12, and 24 for EZ status as normal, patchy, or absent. The thickness of EZ layer in the central subfield was also obtained using machine learning.ResultsEZ assessments were not possible at baseline due to signal blockage in >75% of eyes. At month 1, EZ was normal in 37.6%, patchy in 48.1%, and absent in 14.3%. EZ was measurable in 48.7% with a mean area of 0.07 ± 0.16 mm2. Mean VALS was better in eyes without an EZ defect compared to eyes with an EZ defect (P < 0.0001 at all visits). EZ defect at month 1 was associated with poorer VALS at all follow-up visits (P < 0.0001).ConclusionsBoth qualitative and quantitative assessments of EZ status strongly correlated with VALS. Absence of EZ was associated with poorer VALS at both corresponding and future visits, with larger areas of EZ loss associated with worse VALS.Translational relevanceAssessment of EZ can be used to identify patients with potentially poor response in eyes with retinal vein occlusion.
| S-EPMC7998009 | biostudies-literature
Project description:Background and aims:Pollination by fungus gnats (Mycetophilidae and Sciaridae) is uncommon, but is nevertheless known to occur in 20 genera among eight angiosperm families. Because many fungus gnat-pollinated plants possess a dark red floral display, we hypothesized that fungus gnat pollination is more widespread among plants with similar floral display than currently known. We thus studied the pollination biology of flowers with dark red pigmentation in five families, focusing particularly on plants having small, flat, actinomorphic flowers with exposed nectaries and short stamens, because these floral characteristics mirror those of a known fungus gnat-pollinated genus (Mitella). Methods:We observed daytime and night-time floral visitors for a total of 194.5 h in Aucuba japonica (Garryaceae), Euonymus spp. (Celastraceae), Disanthus cercidifolius (Hamamelidaceae), Micranthes fusca (Saxifragaceae) and Streptopus streptopoides (Liliaceae). Visitors were categorized into functional groups, and a pollination importance index (PII) was calculated for each functional group based on visitation frequency, pollen load and behaviour on flowers. Key results:Fungus gnats were dominant among the 1762 insects observed (36-92 % depending on the plant species) and were the most important pollinators among all plants studied (PII: 0.529-1). Fungus gnat visits occurred during the daytime and, more frequently, at dusk. Most often, pollen grains became clumped on the ventral side of the head and/or thorax as the short-proboscid fungus gnats foraged on nectar and came into contact with anthers located close to the flower base. Conclusions:Pollination by fungus gnats is probably more common than previously thought, especially in habitats similar to those of the plants studied (moist forest understorey, streamside or subalpine meadow) where fungus gnats are abundant year-round. Our results further suggest that there may be a previously unnoticed association between fungus gnat pollination and dark red coloration, and a shared overall floral architecture among the plants studied.
| S-EPMC5853022 | biostudies-literature