WEScover: selection between clinical whole exome sequencing and gene panel testing.
Ontology highlight
ABSTRACT: Background
Whole exome sequencing (WES) is widely adopted in clinical and research settings; however, one of the practical concerns is the potential false negatives due to incomplete breadth and depth of coverage for several exons in clinically implicated genes. In some cases, a targeted gene panel testing may be a dependable option to ascertain true negatives for genomic variants in known disease-associated genes. We developed a web-based tool to quickly gauge whether all genes of interest would be reliably covered by WES or whether targeted gene panel testing should be considered instead to minimize false negatives in candidate genes.Results
WEScover is a novel web application that provides an intuitive user interface for discovering breadth and depth of coverage across population-scale WES datasets, searching either by phenotype, by targeted gene panel(s) or by gene(s). Moreover, the application shows metrics from the Genome Aggregation Database to provide gene-centric view on breadth of coverage.Conclusions
WEScover allows users to efficiently query genes and phenotypes for the coverage of associated exons by WES and recommends use of panel tests for the genes with potential incomplete coverage by WES.
SUBMITTER: Lee IH
PROVIDER: S-EPMC8139020 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Extensive analyses of known monogenic causes of stroke by whole-exome/genome sequencing are technically possible today. We here aimed to compile a comprehensive panel of genes associated with monogenic causes of stroke for use in clinical and research situations. We systematically searched the publically available database Online Mendelian Inheritance in Man, and validated the entries against original peer-reviewed publications in PubMed. First, we selected known pathogenic or putatively pathogenic stroke genes reported in at least one person with stroke, and classified the stroke phenotype for each gene into eight subgroups: (1) large artery atherosclerotic, (2) large artery non-atherosclerotic (tortuosity, dolichoectasia, aneurysm, non-atherosclerotic dissection, occlusion), (3) cerebral small-vessel diseases, (4) cardioembolic (arrhythmia, heart defect, cardiomyopathy), (5) coagulation dysfunctions (venous thrombosis, arterial thrombosis, bleeding tendency), (6) intracerebral hemorrhage, (7) vascular malformations (cavernoma, arteriovenous malformations), and (8) metabolism disorders. Second, we selected other genes that may plausibly cause stroke through diseases related to stroke, but without any documented stroke patient description. A third section comprised SNPs associated with stroke in genome-wide association studies (GWAS). We identified in total 214 genes: 120 associated with stroke, 62 associated with diseases that may cause stroke, and 32 stroke-related genes from recent GWAS. We describe these 214 genes and the clinical stroke subtype(s) associated with each of them. The resulting gene panel can be used to interpret exome sequencing results regarding monogenic stroke. Based on the panel's clinical phenotype description, the pathogenicity of novel variants in these genes may be evaluated in specific situations.
| S-EPMC6336868 | biostudies-literature
Project description:The clinical translation of next-generation sequencing has created a paradigm shift in the diagnostic assessment of individuals with suspected rare genetic diseases. Whole-exome sequencing (WES) simultaneously examines the majority of the coding portion of the genome and is rapidly becoming accepted as an efficient alternative to clinical Sanger sequencing for diagnosing genetically heterogeneous disorders. Among reports of the clinical and diagnostic utility of WES, few studies to date have directly compared its concordance to Sanger sequencing, which is considered the clinical "gold standard". We performed a direct comparison of 391 coding and noncoding polymorphisms and variants of unknown significance identified by clinical Sanger sequencing to the WES results of 26 patients. Of the 150 well-covered coding variants identified by Sanger sequencing, 146 (97.3%) were also reported by WES. Nine genes were excluded from the comparison due to consistently low coverage in WES, which might be attributed to the use of older exome capture kits. We performed confirmatory Sanger sequencing of discordant variants; including five variants with discordant bases and four with discordant zygosity. Confirmatory Sanger sequencing supported the original Sanger report for three of the five discordant bases, one was shown to be a false positive supporting the WES data, and one result differed from both the Sanger and WES data. Two of the discordant zygosity results supported Sanger and the other two supported WES data. We report high concordance for well-covered coding variants, supporting the use of WES as a screening tool for heterogeneous disorders, and recommend the use of supplementary Sanger sequencing for poorly-covered genes when the clinical suspicion is high. Importantly, despite remaining difficulties with achieving complete coverage of the whole exome, 10 (38.5%) of the 26 compared patients were diagnosed through WES.
| S-EPMC5023935 | biostudies-other
Project description:Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders.We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients.We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic phenotypes. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had autosomal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders.Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition. (Funded by the National Human Genome Research Institute.).
| S-EPMC4211433 | biostudies-other
Project description:BackgroundBirth defects are responsible for approximately 7% of neonatal deaths worldwide by World Health Organization in 2004. Many methods have been utilized for examining the congenital anomalies in fetuses. This study aims to investigate the efficiency of simultaneous CNV-seq and whole-exome sequencing (WES) in the diagnosis of fetal anomaly based on a large Chinese cohort.MethodsIn this cohort study, 1800 pregnant women with singleton fetus in Hubei Province were recruited from 2018 to 2020 for prenatal ultrasonic screening. Those with fetal structural anomalies were transferred to the Maternal and Child Health Hospital of Hubei Province through a referral network in Hubei, China. After multidisciplinary consultation and decision on fetal outcome, products of conception (POC) samples were obtained. Simultaneous CNV-seq and WES was conducted to identify the fetal anomalies that can compress initial DNA and turnaround time of reports.ResultsIn total, 959 couples were finally eligible for the enrollment. A total of 227 trios were identified with a causative alteration (CNV or variant), among which 191 (84.14%) were de novo. Double diagnosis of pathogenic CNVs and variants have been identified in 10 fetuses. The diagnostic yield of multisystem anomalies was significantly higher than single system anomalies (32.28% vs. 22.36%, P = 0.0183). The diagnostic rate of fetuses with consistent intra- and extra-uterine phenotypes (172/684) was significantly higher than the rate of these with inconsistent phenotypes (17/116, P = 0.0130).ConclusionsSimultaneous CNV-seq and WES analysis contributed to fetal anomaly diagnosis and played a vital role in elucidating complex anomalies with compound causes.
| S-EPMC8722033 | biostudies-literature
Project description:BackgroundClinical sequencing using a panel of genes has recently been applied worldwide for patients with refractory solid tumors, but the significance of clinical sequencing using gene panel testing remains uncertain. Here we sought to clarify the feasibility and utility of clinical sequencing in the treatment of refractory tumors at our hospital.MethodsA total of 39 patients with advanced solid tumors treated at our hospital between 2018 and 2020 were enrolled in the clinical sequencing. Among them, we identified 36 patients whose tissue samples were of suitable quality for clinical sequencing, and we analyzed the genomic profiles of these tumors.ResultsPathogenic alterations were detected in 28 (78%) of the 36 patients. The most common mutation was TP53 (55%), followed by KRAS (22%), and the highest frequency of gene amplification was ERBB2 (17%). Nine of the 36 patients were identified as candidates for novel molecular-targeted therapy based on their actionable gene alterations, but only one case ended up receiving novel targeted therapy following the genetic tests.ConclusionsOur current results suggested that clinical sequencing might be useful for the detection of pathogenic alterations and the management of additional cancer treatment. However, molecular target based on actionable genomic alteration does not always bridge to subsequent therapy due to clinical deterioration, refusal for unapproved drug, and complexity of clinical trial access. Both improved optimal timing of clinical sequencing and a consensus about its off-label use might help patients receive greater benefit from clinical sequencing.
| S-EPMC7909652 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) is a genetic disorder with an increased risk of early-onset coronary artery disease. Although some clinically diagnosed FH cases are caused by mutations in LDLR, APOB, or PCSK9, mutation detection rates and profiles can vary across ethnic groups. In this study, we aimed to provide insight into the spectrum of FH-causing mutations in Koreans. Among 136 patients referred for FH, 69 who met Simon Broome criteria with definite family history were enrolled. By whole-exome sequencing (WES) analysis, we confirmed that the 3 known FH-related genes accounted for genetic causes in 23 patients (33.3%). A substantial portion of the mutations (19 of 23 patients, 82.6%) resulted from 17 mutations and 2 copy number deletions in LDLR gene. Two mutations each in the APOB and PCSK9 genes were verified. Of these anomalies, two frameshift deletions in LDLR and one mutation in PCSK9 were identified as novel causative mutations. In particular, one novel mutation and copy number deletion were validated by co-segregation in their relatives. This study confirmed the utility of genetic diagnosis of FH through WES.
| S-EPMC4427254 | biostudies-literature
Project description:Whole-exome sequencing provides a cost-effective means to sequence protein coding regions within the genome, which are significantly enriched for etiological variants. We describe a panel of single nucleotide polymorphisms (SNPs) to facilitate the validation of data provenance in whole-exome sequencing studies. This is particularly significant where multiple processing steps necessitate transfer of sample custody between clinical, laboratory and bioinformatics facilities. SNPs captured by all commonly used exome enrichment kits were identified, and filtered for possible confounding properties. The optimised panel provides a simple, yet powerful, method for the assignment of intrinsic, highly discriminatory identifiers to genetic samples.
| S-EPMC3978886 | biostudies-literature
Project description:Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.
| S-EPMC5315517 | biostudies-literature
Project description:BACKGROUND:Clinical diagnostic whole-exome sequencing (WES) is a powerful tool for patients with undiagnosed genetic disorders. To demonstrate the clinical utility, we surveyed healthcare providers (HCP) about changes in medical management and treatment, diagnostic testing, reproductive planning, and use of educational services subsequent to WES testing. METHODS:For a period of 18 months, an 18-question survey was sent to HCPs attached to the WES reports. We analyzed the molecular diagnosis, patient clinical features, and the medical management changes reported in the returned surveys. RESULTS:A total of 62 (2.2% of 2,876) surveys were returned, consisting of 37.1% patients with a positive or likely positive pathogenic alteration, 51.6% negative results, 9.7% uncertain findings, and 1 patient (1.6%) with a novel candidate finding. Overall, 100% of the HCPs of patients with positive or likely positive WES results (n = 23) and HCPs of patients with uncertain WES results (n = 6) responded positively to one of the 18 queries. Of note, 37.5% of the HCPs of patients with negative WES results (n = 32) responded positively to at least one query. CONCLUSION:Overall, these data clearly demonstrate the clinical utility of WES by demonstrating the impact on medical management irrespective of the exome result.
| S-EPMC6305629 | biostudies-literature
Project description:Sanger sequencing, the traditional "gold standard" for mutation detection, has been wildly used in genetic testing of pulmonary artery hypertension (PAH). However, with the advent of whole-exome sequencing (WES), few studies have compared the accuracy of WES and Sanger sequencing in routine genetic testing of PAH. PAH individuals were enrolled from Fu Wai Hospital and Shanghai Pulmonary Hospital. WES was used to analyze DNA samples from 120 PAH patients whose bone morphogenetic protein receptor type 2 (BMPR2) mutation statuses had been previously studied using Sanger sequencing. The Sanger sequencing and WES agreement was 98.3% (118/120) with near-perfect agreement (? coefficient?=?0.848). There was no significant difference between the two methods on the McNemar-Bowker test ( P?>?0.05). Twenty-one BMPR2 mutation carriers and 99 non-carriers were detected by Sanger sequencing. Among the 21 BMPR2 carriers detected by Sanger sequencing, one variant (c.1040 T?>?A) was not found by WES. Among the 99 BMPR2 non-carriers, WES detected an extra mutation carrier (c.76?+?1 G?>?C) missed by Sanger sequencing. Both false-positive and false-negative results were highly conserved and were re-analyzed by Sanger sequencing. WES improved the accuracy of Sanger sequencing and detected 1% (1/99) false-positive and 4.8% (1/21) false-negative results of Sanger sequencing. No false-positive and false-negative results of WES were identified in our analysis. WES is non-inferior to Sanger sequencing and may play a more important role in genetic testing of PAH patients in the future.
| S-EPMC5858635 | biostudies-literature