Panel-based genetic testing for inherited retinal disease screening 176 genes.
Ontology highlight
ABSTRACT: Background
This case series reports the performance of a next-generation sequencing (NGS) panel of 176 retinal genes (NGS 176) in patients with inherited retinal disease (IRD).Methods
Subjects are patients who underwent genetic testing between 1 August 2016 and 1 January 2018 at Moorfields Eye Hospital, London, UK. Panel-based genetic testing was performed unless a specific gene (e.g., RS1) or small group of genes (e.g., ABCA4, PRPH2) were suspected. If a novel variant was identified, a further comment on their predicted pathogenicity and evolutionary conservation was offered and segregation studies performed. The main outcome measure is the likelihood of obtaining a genetic diagnosis using NGS 176.Results
488 patients were included. A molecular diagnosis was obtained for 59.4% of patients. Younger patients were more likely to receive a molecular diagnosis; with 92% of children under the age of 6 years receiving a conclusive result. There was a change in their initially assigned inheritance pattern in 8.4% of patients following genetic testing. Selected IRD diagnoses (e.g., achromatopsia, congenital stationary night blindness) were associated with high diagnostic yields.Conclusion
This study confirms that NGS 176 is a useful first-tier genetic test for most IRD patients. Age and initial clinical diagnosis were strongly associated with diagnostic yield.
SUBMITTER: Sheck LHN
PROVIDER: S-EPMC8683638 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Thirty percent of all inherited retinal disease (IRD) is accounted for by conditions with extra-ocular features. This study aimed to establish the genetic diagnostic pick-up rate for IRD patients with one or more extra-ocular features undergoing panel-based screening in a clinical setting. One hundred and six participants, tested on a gene panel which contained both isolated and syndromic IRD genes, were retrospectively ascertained from the Manchester Genomic Diagnostics Laboratory database spanning 6 years (2012-2017). Phenotypic features were extracted from the clinical notes and classified according to Human Phenotype Ontology; all identified genetic variants were interpreted in accordance to the American College of Medical Genetics and Genomics guidelines. Overall, 49% (n?=?52) of patients received a probable genetic diagnosis. A further 6% (n?=?6) had a single disease-associated variant in an autosomal recessive disease-relevant gene. Fifty-two percent (n?=?55) of patients had a clinical diagnosis at the time of testing. Of these, 71% (n?=?39) received a probable genetic diagnosis. By contrast, for those without a provisional clinical diagnosis (n?=?51), only 25% (n?=?13) received a probable genetic diagnosis. The clinical diagnosis of Usher (n?=?33) and Bardet-Biedl syndrome (n?=?10) was confirmed in 67% (n?=?22) and 80% (n?=?8), respectively. The testing diagnostic rate in patients with clinically diagnosed multisystemic IRD conditions was significantly higher than those without one (71% versus 25%; p value?<?0.001). The lower pick-up rate in patients without a clinical diagnosis suggests that panel-based approaches are unlikely to be the most effective means of achieving a molecular diagnosis for this group. Here, we suggest that genome-wide approaches (whole exome or genome) are more appropriate.
| S-EPMC7171123 | biostudies-literature
Project description:This paper investigates the willingness of adults with inherited retinal disease to undergo and pay for diagnostic genetic testing in three hypothetical scenarios and to explore the factors that influence decision making. Fifty patients were presented with three scenarios whereby genetic testing provided increasing information: confirming the diagnosis and inheritance pattern alone, providing additional information on future visual function, and identifying in addition a new treatment which could stabilise their condition. Willingness to pay (WTP) was elicited using an iterative bidding game. Regression analysis was used to investigate the probability of agreeing to and paying for testing. Qualitative data were also reviewed to provide a comprehensive understanding of WTP and decision making. The majority of participants agreed to undergo genetic testing in each of the three scenarios. Scenario 2 was the least acceptable with 78% of participants agreeing to genetic testing. The probability of agreeing to genetic testing decreased with age. Between 72 and 96% of participants reported a WTP for genetic testing. Average WTP was £539, £1516, and £6895 for scenarios 1, 2, and 3 respectively. Older participants and participants with higher incomes were willing to pay more for testing. Qualitative data provided additional detail about the rationale behind participants' decisions. The study suggests that patients with inherited retinal disease were willing to undergo and to pay for diagnostic genetic testing, suggesting that they valued the information it may provide. However, several patients preferred not to receive prognostic information and were less willing to pay for genetic testing that yielded such detail.
| S-EPMC4326707 | biostudies-other
Project description:BackgroundDisease severity is important when considering genes for inclusion on reproductive expanded carrier screening (ECS) panels. We applied a validated and previously published algorithm that classifies diseases into four severity categories (mild, moderate, severe, and profound) to 176 genes screened by ECS. Disease traits defining severity categories in the algorithm were then mapped to four severity-related ECS panel design criteria cited by the American College of Obstetricians and Gynecologists (ACOG).MethodsEight genetic counselors (GCs) and four medical geneticists (MDs) applied the severity algorithm to subsets of 176 genes. MDs and GCs then determined by group consensus how each of these disease traits mapped to ACOG severity criteria, enabling determination of the number of ACOG severity criteria met by each gene.ResultsUpon consensus GC and MD application of the severity algorithm, 68 (39%) genes were classified as profound, 71 (40%) as severe, 36 (20%) as moderate, and one (1%) as mild. After mapping of disease traits to ACOG severity criteria, 170 out of 176 genes (96.6%) were found to meet at least one of the four criteria, 129 genes (73.3%) met at least two, 73 genes (41.5%) met at least three, and 17 genes (9.7%) met all four.ConclusionThis study classified the severity of a large set of Mendelian genes by collaborative clinical expert application of a trait-based algorithm. Further, it operationalized difficult to interpret ACOG severity criteria via mapping of disease traits, thereby promoting consistency of ACOG criteria interpretation.
| S-EPMC7540025 | biostudies-literature
Project description:BackgroundIn this study, we aim to investigate the awareness of, attitudes toward, and experiences with diagnostic genetic testing among parents of children suspected of having inherited retinal disease (IRDs) in China.MethodsSemistructured, face-to-face, and in-depth interviews were carried out with parents of children with suspected IRDs in this qualitative study. Inductive content analysis was used for data processing.ResultsForty-six parents participated in our interviews, and 47.8% of them supported genetic testing for following four main reasons: to help in making informed reproductive health decisions, to prepare for novel potential treatment, to identify the underlying causes of IRDs, and to satisfy curiosity about the heredity of IRDs. Among them, 19.6% were opposed to the testing for four main reasons, namely lack of therapeutic benefit, difficulty in affording the testing cost, doubt in the accuracy of clinical diagnosis, and the presence of concerns about the limitations of genetic testing. 47.8% of the parents expressed concerns that the genetic findings might lead to potential psychological stress.ConclusionIn this study, we showed that nearly half of the parents supported genetic testing mainly for family planning, and a fifth of the parents were opposed to the testing mainly for lack of therapeutic benefit. Moreover, half of the parents expressed concern that a positive genetic result may create potential psychological burden to the parents and children.
| S-EPMC6732314 | biostudies-literature
Project description:The overlapping genetic and clinical spectrum in inherited retinal degeneration (IRD) creates challenges for accurate diagnoses. The goal of this work was to determine the genetic diagnosis and clinical features for patients diagnosed with an IRD. After signing informed consent, peripheral blood or saliva was collected from 64 patients diagnosed with an IRD. Genetic testing was performed on each patient in a Clinical Laboratory Improvement Amendments of 1988 (CLIA) certified laboratory. Mutations were verified with Sanger sequencing and segregation analysis when possible. Visual acuity was measured with a traditional Snellen chart and converted to a logarithm of minimal angle of resolution (logMAR). Fundus images of dilated eyes were acquired with the Optos® camera (Dunfermline, UK). Horizontal line scans were obtained with spectral-domain optical coherence tomography (SDOCT; Spectralis, Heidelberg, Germany). Genetic testing combined with segregation analysis resolved molecular and clinical diagnoses for 75% of patients. Ten novel mutations were found and unique genotype phenotype associations were made for the genes RP2 and CEP83. Collective knowledge is thereby expanded of the genetic basis and phenotypic correlation in IRD.
| S-EPMC9859429 | biostudies-literature
Project description:Although rare, inherited retinal degenerations (IRDs) are the most common reason for blind registration in the working age population. They are highly genetically heterogeneous (>300 known genetic loci), and confirmation of a molecular diagnosis is a prerequisite for many therapeutic clinical trials and approved treatments. First-tier genetic testing of IRDs with panel-based next-generation sequencing (pNGS) has a diagnostic yield of ≈70-80%, leaving the remaining more challenging cases to be resolved by second-tier testing methods. This study describes the phenotypic reassessment of patients with a negative result from first-tier pNGS and the rationale, outcomes, and cost of second-tier genetic testing approaches. Removing non-IRD cases from consideration and utilizing case-appropriate second-tier genetic testing techniques, we genetically resolved 56% of previously unresolved pedigrees, bringing the overall resolve rate to 92% (388/423). At present, pNGS remains the most cost-effective first-tier approach for the molecular assessment of diverse IRD populations Second-tier genetic testing should be guided by clinical (i.e., reassessment, multimodal imaging, electrophysiology), and genetic (i.e., single alleles in autosomal recessive disease) indications to achieve a genetic diagnosis in the most cost-effective manner.
| S-EPMC8780304 | biostudies-literature
Project description:Retinal dystrophy (RD) is a broad group of hereditary disorders with heterogeneous genotypes and phenotypes. Current available genetic testing for these diseases is complicated, time consuming, and expensive. This study was conducted to develop and apply a microarray-based, high-throughput resequencing system to detect sequence alterations in genes related to inherited RD.A customized 300-kb resequencing chip, Retina-Array, was developed to detect sequence alterations of 267,550 bases of both sense and antisense sequence in 1470 exons spanning 93 genes involved in inherited RD. Retina-Array was evaluated in 19 patient samples with inherited RD provided by the eyeGENE repository and four Centre d'Etudes du Polymorphisme Humaine reference samples through a high-throughput experimental approach that included an automated PCR assay setup and quantification, efficient post-quantification data processing, optimized pooling and fragmentation, and standardized chip processing.The performance of the chips demonstrated that the average base pair call rate and accuracy were 93.56% and 99.86%, respectively. In total, 304 candidate variations were identified using a series of customized screening filters. Among 174 selected variations, 123 (70.7%) were further confirmed by dideoxy sequencing. Analysis of patient samples using Retina-Array resulted in the identification of 10 known mutations and 12 novel variations with high probability of deleterious effects.This study suggests that Retina-Array might be a valuable tool for the detection of disease-causing mutations and disease severity modifiers in a single experiment. Retinal-Array may provide a powerful and feasible approach through which to study genetic heterogeneity in retinal diseases.
| S-EPMC3231844 | biostudies-literature
Project description:AimTo test the utility of targeted sequencing as a method of clinical molecular testing in patients diagnosed with inherited retinal degeneration (IRD).MethodsAfter genetic counseling, peripheral blood was drawn from 188 probands and 36 carriers of IRD. Single gene testing was performed on each patient in a Clinical Laboratory Improvement Amendment (CLIA) certified laboratory. DNA was isolated, and all exons in the gene of interest were analyzed along with 20 base pairs of flanking intronic sequence. Genetic testing was most often performed on ABCA4, CTRP5, ELOV4, BEST1, CRB1, and PRPH2. Pathogenicity of novel sequence changes was predicted by PolyPhen2 and sorting intolerant from tolerant (SIFT).ResultsOf the 225 genetic tests performed, 150 were for recessive IRD, and 75 were for dominant IRD. A positive molecular diagnosis was made in 70 (59%) of probands with recessive IRD and 19 (26%) probands with dominant IRD. Analysis confirmed 12 (34%) of individuals as carriers of familial mutations associated with IRD. Thirty-two novel variants were identified; among these, 17 sequence changes in four genes were predicted to be possibly or probably damaging including: ABCA4 (14), BEST1 (2), PRPH2 (1), and TIMP3 (1).ConclusionsTargeted analysis of clinically suspected genes in 225 subjects resulted in a positive molecular diagnosis in 26% of patients with dominant IRD and 59% of patients with recessive IRD. Novel damaging mutations were identified in four genes. Single gene screening is not an ideal method for diagnostic testing given the phenotypic and genetic heterogeneity among IRD cases. High-throughput sequencing of all genes associated with retinal degeneration may be more efficient for molecular diagnosis.
| S-EPMC5327051 | biostudies-literature
Project description:BackgroundNext-generation sequencing (NGS)-based method is being used broadly for genetic testing especially for clinically and genetically heterogeneous disorders, such as inherited retinal degenerations (IRDs) but still not routinely used for molecular diagnostics in Bulgaria. Consequently, the purpose of this study was to evaluate the effectiveness of a molecular diagnostic approach, based on targeted NGS for the identification of the disease-causing mutations in 16 Bulgarian patients with different IRDs.MethodsWe applied a customized NGS panel, including 125 genes associated with retinal and other eye diseases to the patients with hereditary retinopathies.ResultsSystematic filtering approach coupled with copy number variation analysis and segregation study lead to the identification of 16 pathogenic and likely pathogenic variants in 12/16 (75%) of IRD patients, 2 of which novel (12.5%): ABCA4-c.668delA (p.K223Rfs18) and RР1-c.2015dupA (p.K673Efs*25). Mutations in the ABCA4, PRPH2, USH2A, BEST1, RР1, CDHR1, and RHO genes were detected reaching a diagnostic yield between 42.9% for Retinitis pigmentosa cases and 100% for macular degeneration, Usher syndrome, and cone-rod dystrophy patients.ConclusionOur results confirm the usefulness of targeted NGS approach based on frequently mutated genes as a comprehensive and successful genetic diagnostic tool for IRDs with significant impact on patients counseling.
| S-EPMC9356554 | biostudies-literature
Project description:BackgroundNext-generation sequencing (NGS) is a useful tool for evaluating patients with suspected genetic kidney disease. Clinical practice relies on the use of targeted gene panels that are ordered based on patient presentation. We compare the diagnostic yield of clinical panel-based testing to exome analysis.MethodsIn total, 324 consecutive patients underwent physician-ordered, panel-based NGS testing between December 2014 and October 2018. Gene panels were available for four clinical phenotypes, including atypical hemolytic uremic syndrome (n=224), nephrotic syndrome (n=56), cystic kidney disease (n=26), and Alport syndrome (n=13). Variants were analyzed and clinical reports were signed out by a pathologist or clinical geneticist at the time of testing. Subsequently, all patients underwent retrospective exome analysis to detect additional clinically significant variants in kidney disease genes that were not analyzed as part of the initial clinical gene panel. Resulting variants were classified according to the American College of Medical Genetics and Genomics 2015 guidelines.ResultsIn the initial physician-ordered gene panels, we identified clinically significant pathogenic or likely pathogenic variants in 13% of patients (n=42/324). CFHR3-CFHR1 homozygous deletion was detected in an additional 13 patients with aHUS without a pathogenic or likely pathogenic variant. Diagnostic yield of the initial physician-ordered gene panel was 20% and varied between groups. Retrospective exome analysis identified 18 patients with a previously unknown pathogenic or likely pathogenic variant in a kidney disease gene and eight patients with a high-risk APOL1 genotype. Overall, retrospective exome analysis increased the diagnostic yield of panel-based testing from 20% to 30%.ConclusionsThese results highlight the importance of a broad and collaborative approach between the clinical laboratory and their physician clients that employs additional analysis when a targeted panel of kidney disease-causing genes does not return a clinically meaningful result.
| S-EPMC8815744 | biostudies-literature