Improving graph-based OCT segmentation for severe pathology in Retinitis Pigmentosa patients.
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ABSTRACT:
SUBMITTER: Lang A
PROVIDER: S-EPMC5540322 | biostudies-other | 2017 Feb
REPOSITORIES: biostudies-other
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Project description:PurposeTo report a severe phenotype of retinitis pigmentosa associated with novel mutations in CNGB1.ObservationsSix siblings, age range 50-75 years old, were examined using optical coherence tomography and fundus autofluorescene, electroretinogram testing, Goldman visual field testing, and genetic testing using next generation sequencing.In four affected siblings, two novel compound heterozygous variants in CNGB1 were detected: in exon 26 the missense variant c.2603G > A (p.(Gly868Asp)), and in exon 21, the in-frame 12-bp duplication c.2093_2104dupGCGACCTCATCT (p.(Cys698_lle701dup)). One sibling was unaffected and carried neither of the variants, while another sibling had mild macular degeneration changes and carried the latter variant in heterozygous status. The affected siblings presented with a phenotype showing markedly constricted visual field, flat scotopic and photopic electroretinogram responses and generalized retinal atrophy.Conclusions and importanceThis is the first report of a 12bp in-frame duplication and a missense variant (in compound heterozygous status) in CNGB1, being associated with a severe form of retinitis pigmentosa featuring extensive peripheral and central retinal degeneration. This study expands the molecular genetic basis of CNGB1-related disease.
| S-EPMC7315105 | biostudies-literature
Project description:PurposeWe investigate the ellipsoid zone (EZ) area and EZ boundary shape measurement reliability and the operability characteristics of two methods of EZ boundary delineation in spectral-domain optical coherence tomography (SD-OCT).MethodsEZ boundaries in SD-OCT scans of 122 eyes from 64 subjects with autosomal dominant retinitis pigmentosa were delineated by three raters using two methods, termed the profile and en face methods. For each method, we determined the measurement reliabilities for boundary area (EZ area) and boundary shape, percentage of eyes with measurable EZ (measurability), time required, and effect of rater experience.ResultsWith expert raters, inter- and intrarater area intraclass correlation coefficients (ICCs) were 0.986 and 0.980 (profile) and 0.959 and 0.976 (en face), respectively. In comparison, the corresponding shape ICCs were 0.906 and 0.891 (profile) and 0.845 and 0.885 (en face), indicating lower reliability for the raw measurements (P ≤ 0.01). Only profile method interrater reliability depended on experience. Average measurement times per eye were 8.2 (profile) and 4.1 (en face) minutes. Measurability percentages were 99.2% (profile) and 73.0% (en face).ConclusionsThe slower profile method had better measurability, and with expert raters yielded the best area and shape reliabilities. The faster, but less sensitive, en face method still showed excellent reliability, and was less dependent on experience. Shape analysis reveals the boundary measurements underpinning EZ area have lower reliability than suggested by area analysis.Translational relevanceThis study provides new reliability perspectives and logistical considerations for the manual measurement procedures that generate EZ area outcome measures.
| S-EPMC6561133 | biostudies-literature
Project description:PurposeTo compare the efficacy of frequency domain optical coherence tomography (fdOCT)-derived outer retinal measures in tracking disease progression in x-linked (xl) retinitis pigmentosa (RP) patients.MethodsMacular volume scans and line scans (Spectralis) were obtained from 27 xlRP patients (15.3 ± 6.4 years) at two visits approximately 2 years apart. Changes in average outer retinal layer thicknesses across the volume scan were compared to changes detected by measures derived from the edge of the inner segment ellipsoid zone (EZ) band, that is, where the EZ band (also known as inner segment/outer segment border) disappears. Repeatability was tested on an independent set of 18 RP patients (43.5 ± 18.0 years).ResultsAverage outer segment (OS) and outer nuclear layer (ONL) thickness showed marginally significant annual changes (P < 0.05), while total receptor (TR) thickness showed a greater change (P < 0.01). All measures derived from the edge of the EZ band significantly decreased (P < 0.01). Mean ± SD for test-retest differences in horizontal widths was 0.01 ± 0.06 mm.ConclusionsMeasures of the EZ band are more effective in detecting disease progression than are thickness measures. Given the similar effectiveness of line and volume scans, manually marking the EZ band edge on vertical and/or horizontal line scans can be useful in tracking progression.Translational relevanceBecause disease progression in RP can be relatively slow, annual changes can be difficult to monitor during the course of a clinical trial. Here we suggest a quick, effective, and reliable method for detecting subtle changes.
| S-EPMC3860354 | biostudies-literature
Project description:PurposeUsing quantitative fundus autofluorescence (qAF), we analyzed short-wavelength autofluorescent (SW-AF) rings in RP.MethodsShort-wavelength autofluorescent images (486 nm excitation) of 40 patients with RP (69 eyes) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference. Mean qAF was measured in eight preset segments (qAF8) and in region of interest (ROI)-qAF (200-700 μm) within and external to the borders of the rings at superior, temporal, and inferior sites relative to the ring. For both groups, qAF in patients with RP was compared to age-similar and race/ethnicity-matched healthy eyes at equivalent retinal locations.ResultsIn 71% of eyes of RP patients, qAF8 acquired internal to the inner border of the ring, was within the 95% confidence interval (CI) for healthy eyes, while in the remaining RP eyes qAF8 was either higher or lower than the CI. Measured external to the ring, qAF8 values were within the CI in 47% of RP eyes with the other eyes being higher or lower. In 28% of sites measured by ROI-qAF within the SW-AF ring, values were above the 95% CI of healthy controls. Region of interest-qAF measured just external to the ring was within the CI of healthy eyes in 74% of locations. The average local elevation in qAF within the ring was approximately 15%. In SD-OCT scans, photoreceptor-attributable reflectivity bands were thinned within and external to the ring.ConclusionsIncreased fluorophore production may be a factor in the formation of the SW-AF rings in RP.
| S-EPMC5377994 | biostudies-literature
Project description:AimTo investigate the prevalence of macular abnormalities in a large Caucasian cohort of patients affected by retinitis pigmentosa (RP).MethodsA retrospective study was performed by reviewing the medical records and optical coherence tomography (OCT) scans in a cohort of 581 RP patients in order to assess the presence of macular abnormalities -that is, cystoid macular oedema (CMO), epiretinal membrane (ERM), vitreo-macular traction syndrome, and macular hole.ResultsMacular abnormalities were observed in 524 (45.1%) out of the 1161 examined eyes. The most frequent abnormality was CMO, observed in 237 eyes (20.4%) from 133 patients (22.9%), followed by ERM, assessed in 181 eyes (15.6%) from 115 patients (19.8%). Moreover, vitreo-retinal abnormalities were significantly (p<0.05) associated with older age, cataract surgery, or cataract. CMO appeared to be significantly (p<0.05) associated with female gender, autosomic dominant inheritance pattern, and cataract.ConclusionsMacular abnormalities are more frequent in RP compared to the general population. For that reason, screening RP patients with OCT is highly recommended to follow-up the patients, evaluate the natural history of disease, and identify those patients who could benefit from current or innovative therapeutic strategies.
| S-EPMC4078675 | biostudies-literature
Project description:PurposeTo evaluate microarray-based genotyping technology for the detection of mutations responsible for retinitis pigmentosa (RP) and to perform phenotypic characterization of patients with pathogenic mutations.MethodsDNA from 336 patients with RP and 360 controls was analyzed using the GoldenGate assay with microbeads containing 95 previously reported disease-associated mutations from 28 RP genes. Mutations identified by microarray-based genotyping were confirmed by direct sequencing. Segregation analysis and phenotypic characterization were performed in patients with mutations. The disease severity was assessed by visual acuity, electroretinography, optical coherence tomography, and kinetic perimetry.ResultsTen RP-related mutations of five RP genes (PRP3 pre-mRNA processing factor 3 homolog [PRPF3], rhodopsin [RHO], phosphodiesterase 6B [PDE6B], peripherin 2 [PRPH2], and retinitis pigmentosa 1 [RP1]) were identified in 26 of the 336 patients (7.7%) and in six of the 360 controls (1.7%). The p.H557Y mutation in PDE6B, which was homozygous in four patients and heterozygous in nine patients, was the most frequent mutation (2.5%). Mutation segregation was assessed in four families. Among the patients with missense mutations, the most severe phenotype occurred in patients with p.D984G in RP1; less severe phenotypes occurred in patients with p.R135W in RHO; a relatively moderate phenotype occurred in patients with p.T494M in PRPF3, p.H557Y in PDE6B, or p.W316G in PRPH2; and a mild phenotype was seen in a patient with p.D190N in RHO.ConclusionsThe results reveal that the GoldenGate assay may not be an efficient method for molecular diagnosis in RP patients with rare mutations, although it has proven to be reliable and efficient for high-throughput genotyping of single-nucleotide polymorphisms. The clinical features varied according to the mutations. Continuous effort to identify novel RP genes and mutations in a population is needed to improve the efficiency and accuracy of the genetic diagnosis of RP.
| S-EPMC3462597 | biostudies-literature
Project description:Pericentral retinitis pigmentosa (RP) is an atypical form of RP that affects the near-peripheral retina first and tends to spare the far periphery. This study was performed to further define the genetic basis of this phenotype. We identified a cohort of 43 probands with pericentral RP based on a comprehensive analysis of their retinal phenotype. Genetic analyses of DNA samples from these patients were performed using panel-based next-generation sequencing, copy number variations, and whole exome sequencing (WES). Mutations provisionally responsible for disease were found in 19 of the 43 families (44%) analyzed. These include mutations in RHO (five patients), USH2A (four patients), and PDE6B (two patients). Of 28 putatively pathogenic alleles, 15 (54%) have been previously identified in patients with more common forms of typical RP, while the remaining 13 mutations (46%) were novel. Burden testing of WES data successfully identified HGSNAT as a cause of pericentral RP in at least two patients, suggesting it is also a relatively common cause of pericentral RP. While additional sequencing might uncover new genes specifically associated with pericentral RP, the current results suggest that genetically pericentral RP is not a separate clinical entity, but rather is part of the spectrum of mild RP phenotypes.
| S-EPMC5664106 | biostudies-literature
Project description:BackgroundRetinal dystrophies constitute a group of diseases characterized by clinical variability and pronounced genetic heterogeneity. Retinitis pigmentosa is the most common subtype of hereditary retinal dystrophy and is characterized by a progressive loss of peripheral field vision (Tunnel Vision), eventual loss of central vision, and progressive night blindness. The characteristics of the fundus changes include bone-spicule formations, attenuated blood vessels, reduced and/or abnormal electroretinograms, changes in structure imaged by optical coherence tomography, and subjective changes in visual function. The different syndromic and nonsyndromic forms of retinal dystrophies can be attributed to mutations in more than 250 genes. Molecular diagnosis for patients with retinitis pigmentosa has been hampered by extreme genetic and clinical heterogeneity between retinitis pigmentosa and other forms of retinal dystrophies. Next generation sequencing (NGS) technologies are among the most promising techniques to identify pathogenic variations in retinal dystrophies.PurposeThe purpose of this study was to discover the molecular diagnosis for Brazilian patients clinically diagnosed with a retinitis pigmentosa pattern of inheritance by using NGS technologies.Materials and methodsSixteen patients with the clinical diagnosis of retinitis pigmentosa were included in the study. Their DNA was sequenced in a panel with 132 genes related to retinal dystrophies using the Illumina® platform. Sequence analysis and variation calling was performed using Soft Genetics®, NextGene, and Geneticist Assistant software. The criteria for pathogenicity analysis were established according to the results of prediction programs (Polyphen 2, Mutation taster and MetaCore™) and comparison of pathogenic variations found with databases.ResultsThe identified potentially pathogenic variations were all confirmed by Sanger sequencing. There were 89 variations predicted as pathogenic, but only 10 of them supported the conclusion of the molecular diagnosis. Five of the nine patients were autosomal dominant RP (56%), two (22%) were autosomal recessive RP, and two (22%) were X-linked RP. Nine of the 16 patients (56%) had probably positive or positive results.ConclusionThe Next Generation Sequencing used in this study allowed the molecular diagnosis to be confirmed in 56% of the patients and clarified the inheritance pattern of the patient's retinal dystrophies.
| S-EPMC5592712 | biostudies-literature
Project description:ImportanceCo-occurrence of retinitis pigmentosa (RP) and olfactory dysfunction may have a common genetic cause.ObjectiveTo report olfactory function and the retinal phenotype in patients with biallelic mutations in CNGB1, a gene coding for a signal transduction channel subunit expressed in rod photoreceptors and olfactory sensory neurons.Design, setting, and participantsThis case series was conducted from August 2015 through July 2017. The setting was a multicenter study involving 4 tertiary referral centers for inherited retinal dystrophies. Participants were 9 patients with CNGB1-associated RP.Main outcomes and measuresResults of olfactory testing, ocular phenotyping, and molecular genetic testing using targeted next-generation sequencing.ResultsNine patients were included in the study, 3 of whom were female. Their ages ranged between 34 and 79 years. All patients had an early onset of night blindness but were usually not diagnosed as having RP before the fourth decade because of slow retinal degeneration. Retinal features were characteristic of a rod-cone dystrophy. Olfactory testing revealed reduced or absent olfactory function, with all except one patient scoring in the lowest quartile in relation to age-related norms. Brain magnetic resonance imaging and electroencephalography measurements in response to olfactory stimulation were available for 1 patient and revealed no visible olfactory bulbs and reduced responses to odor, respectively. Molecular genetic testing identified 5 novel (c.1312C>T, c.2210G>A, c.2492+1G>A, c.2763C>G, and c.3044_3050delGGAAATC) and 5 previously reported mutations in CNGB1.Conclusions and relevanceMutations in CNGB1 may cause an autosomal recessive RP-olfactory dysfunction syndrome characterized by a slow progression of retinal degeneration and variable anosmia or hyposmia.
| S-EPMC6136054 | biostudies-literature
Project description:BackgroundMERTK (MER proto-oncogene, tyrosine kinase) is a transmembrane protein essential in regulating photoreceptor outer segment phagocytosis. Biallelic mutations in MERTK cause retinal degeneration. Here we present the retinal phenotype of three patients with missense variants in MERTK.Materials and methodsAll patients underwent a full clinical examination, fundus photography, short-wavelength fundus autofluorescence and optical coherence tomography imaging. Two patients also underwent Goldmann visual field testing and electroretinography was undertaken for the third patient. Molecular genetic testing was undertaken using next generation or whole-exome sequencing with all variants confirmed by Sanger sequencing.ResultsThe first patient was a 29-year-old female heterozygous for a missense variant (c.1133C>T, p.Thr378 Met) and a nonsense variant (c.1744_1751delinsT, p.Ile582Ter) in MERTK. The second patient was a 26-year-old male homozygous for a c.2163T>A, p.His721Gln variant in MERTK. The third patient was an 11-year-old female heterozygous for a deletion of exons 5-19 and a missense variant (c.1866 G>C, p.Lys622Asn) in MERTK. Reduced night vision was the initial symptom in all patients. Fundoscopy revealed typical signs of retinitis pigmentosa (RP) with early-onset macular atrophy. All three MERTK missense variants affect highly conserved residues within functional domains, have low population frequencies and are predicted to be pathogenic in silico.ConclusionsWe report three missense variants in MERTK and present the associated phenotypic data, which are supportive of non-syndromic RP. MERTK is a promising candidate for viral-mediated gene replacement therapy. Moreover, one variant represents a single nucleotide transition, which is theoretically targetable with CRISPR-Cas9 base-editing.
| S-EPMC9615558 | biostudies-literature