scholarly journals Prospective evaluation of genome sequencing versus standard-of-care as a first molecular diagnostic test

2020 ◽  
Author(s):  
Deanna G Brockman ◽  
Christina A Austin-Tse ◽  
Renée C Pelletier ◽  
Caroline Harley ◽  
Candace Patterson ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Genome Sequencing ◽  
Genetic Test ◽  
Massachusetts General Hospital ◽  
Diagnostic Yield ◽  
Randomized Study ◽  
Standard Of Care ◽  
Turnaround Time ◽  
Molecular Diagnostic ◽  
Implementation Challenges

Abstract Purpose: To evaluate the diagnostic yield and clinical utility of clinical genome sequencing (cWGS) as a first genetic test for patients with suspected monogenic disorders. Methods: We conducted a prospective randomized study with pediatric and adult patients recruited from genetics clinics at Massachusetts General Hospital who were undergoing planned genetic testing. Participants were randomized into two groups: standard-of-care genetic testing (SOC) only or SOC and cWGS. Results: 204 participants were enrolled and 99 received cWGS. cWGS returned 23 molecular diagnoses in 20 individuals: A diagnostic yield of 20% (20/99, 95%CI 12.3-28.1%)), which was not significantly different from SOC (17%, 95%CI 9.7%-24.6%, P=0.584). 19/23 cWGS diagnoses provided an explanation for clinical features or were considered worthy of additional workup by referring providers. While cWGS detected all variants reported by SOC, SOC failed to capture 9/23 cWGS diagnoses; primarily due to genes not included in SOC tests. Turnaround time was significantly shorter for SOC compared to cWGS (33.9 days vs 87.2 days, P<0.05). Conclusions: cWGS is technically suitable as a first genetic test and identified clinically relevant variants not captured by SOC. However, further studies addressing other variant types and implementation challenges are needed to support feasibility of its broad-scale adoption.

scholarly journals A Simple Practical Guide to Genomic Diagnostics in a Pediatric Setting

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 818
Author(s):  
Alan Taylor ◽  
Zeinab Alloub ◽  
Ahmad Abou Tayoun
Keyword(s):  
Genetic Testing ◽  
Genetic Test ◽  
Diagnostic Yield ◽  
Financial Burden ◽  
Healthcare Providers ◽  
Cost Effective ◽  
Turnaround Time ◽  
Test Characteristics ◽  
Clinical Scenarios ◽  
Uncertain Significance

With limited access to trained clinical geneticists and/or genetic counselors in the majority of healthcare systems globally, and the expanding use of genetic testing in all specialties of medicine, many healthcare providers do not receive the relevant support to order the most appropriate genetic test for their patients. Therefore, it is essential to educate all healthcare providers about the basic concepts of genetic testing and how to properly utilize this testing for each patient. Here, we review the various genetic testing strategies and their utilization based on different clinical scenarios, and test characteristics, such as the types of genetic variation identified by each test, turnaround time, and diagnostic yield for different clinical indications. Additional considerations such as test cost, insurance reimbursement, and interpretation of variants of uncertain significance are also discussed. The goal of this review is to aid healthcare providers in utilizing the most appropriate, fastest, and most cost-effective genetic test for their patients, thereby increasing the likelihood of a timely diagnosis and reducing the financial burden on the healthcare system by eliminating unnecessary and redundant testing.

scholarly journals Randomized prospective evaluation of genome sequencing versus standard-of-care as a first molecular diagnostic test

2021 ◽  
Author(s):  
Deanna G. Brockman ◽  
Christina A. Austin-Tse ◽  
Renée C. Pelletier ◽  
Caroline Harley ◽  
Candace Patterson ◽  
...  
Keyword(s):  
Diagnostic Test ◽  
Genome Sequencing ◽  
Standard Of Care ◽  
Molecular Diagnostic ◽  
Prospective Evaluation ◽  
Molecular Diagnostic Test

scholarly journals Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test

2017 ◽  
Vol 20 (4) ◽  
pp. 435-443 ◽  
Author(s):  
Anath C Lionel ◽  
Gregory Costain ◽  
Nasim Monfared ◽  
Susan Walker ◽  
Miriam S Reuter ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Test ◽  
Diagnostic Yield ◽  
Gene Sequencing ◽  
Whole Genome ◽  
Targeted Gene Sequencing

Facilitated cascade testing (FaCT): a randomized controlled trial

2020 ◽  
pp. ijgc-2020-002118
Author(s):  
Roni Nitecki ◽  
Haley A Moss ◽  
Catherine H Watson ◽  
Diana L Urbauer ◽  
Alexander Melamed ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Controlled Trial ◽  
Randomized Study ◽  
Standard Of Care ◽  
Pathogenic Mutation ◽  
Primary Objective ◽  
Care Group ◽  
Patient Navigator ◽  
Cascade Testing ◽  
First Degree Relatives

BackgroundIdentifying mutation-carrying relatives of patients with hereditary cancer syndromes via cascade testing is an underused first step in primary cancer prevention. A feasibility study of facilitated genetic testing of at-risk relatives of patients with a known pathogenic mutation demonstrated encouraging uptake of cascade testing.Primary objectiveOur primary objective is to compare the proportion of genetic testing of identified first-degree relatives of probands with a confirmed BRCA1/2 mutation randomized to a facilitated cascade testing strategy versus standard of care, proband-mediated, information sharing.Study hypothesisWe hypothesize that facilitated cascade testing will drive significantly higher uptake of genetic testing than the standard of care.Trial designThe FaCT (Facilitated Cascade Testing) trial is a prospective multi-institutional randomized study comparing the efficacy of a multicomponent facilitated cascade testing intervention with the standard of care. Patients with a known BRCA1/2 mutation (probands) cared for at participating sites will be randomized. Probands randomized to the standard of care group will be instructed to share a family letter with their first-degree relatives and encourage them to complete genetic testing. First-degree relatives of probands randomized to the intervention arm will receive engagement strategies with a patient navigator, an educational video, and accessible genetic testing services.Major inclusion/exclusion criteriaAdult participants who are first-degree relatives of a patient with a BRCA1/2 mutation and have not had prior genetic testing will be included.Primary endpointAnalyses will assess the proportion of first-degree relatives identified by the proband who complete genetic testing by 6 months in the intervention arm versus the control arm.Sample sizeOne hundred and fifty probands with a BRCA1/2 mutation will be randomized. Each proband is expected to provide an average of 3 relatives, for an expected 450 participants.Estimated dates for completing accrual and presenting resultsJanuary 2024.Trial registrationNCT04613440

scholarly journals Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease

Ophthalmology ◽  
2016 ◽  
Vol 123 (5) ◽  
pp. 1143-1150 ◽  
Author(s):  
Jamie M. Ellingford ◽  
Stephanie Barton ◽  
Sanjeev Bhaskar ◽  
Simon G. Williams ◽  
Panagiotis I. Sergouniotis ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Diagnostic Yield ◽  
Diagnostic Testing ◽  
Retinal Disease ◽  
Molecular Diagnostic ◽  
Whole Genome ◽  
Inherited Retinal Disease

scholarly journals Clinical Utility of Exome Sequencing and Reinterpreting Genetic Test Results in Children and Adults With Epilepsy

2020 ◽  
Vol 11 ◽  
Author(s):  
Yong-li Jiang ◽  
Changgeng Song ◽  
Yuanyuan Wang ◽  
Jingjing Zhao ◽  
Fang Yang ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Clinical Utility ◽  
Genetic Test ◽  
Diagnostic Yield ◽  
Clinical Information ◽  
Test Results ◽  
Diagnostic Potential ◽  
Genetic Test Results ◽  
Diagnosis Rate ◽  
Clinically Significant

The clinical utility of genetic testing for epilepsy has been enhanced with the advancement of next-generation sequencing (NGS) technology along with the rapid updating of publicly available databases. The aim of this study was to evaluate the diagnostic yield of NGS and assess the value of reinterpreting genetic test results in children and adults with epilepsy. We performed genetic testing on 200 patients, including 82 children and 118 adults. The results were classified into three categories: positive, inconclusive, or negative. The reinterpretation of inconclusive results was conducted in April 2020. Overall, we identified disease-causing variants in 12% of the patients in the original analysis, and 14.5% at reinterpretation. The diagnostic yield for adults with epilepsy was similar to that for children (11 vs. 19.5%, p = 0.145). After reinterpretation, 9 of the 86 patients who initially had inconclusive results obtained a clinically significant change in diagnosis. Among these nine revised cases, five obtained positive diagnoses, representing a diagnosis rate of 5.8% (5/86). Manual searches for additional evidence of pathogenicity for candidate variants and updated patient clinical information were the main reasons for diagnostic reclassification. This study emphasizes the diagnostic potential of combining NGS and reinterpretation of inconclusive genetic test reports in children and adults with epilepsy.

scholarly journals THE ROLE OF WHOLE GENOME SEQUENCING AS A DIAGNOSTIC TOOL FOR CHILDREN WITH MEDICAL COMPLEXITY

2018 ◽  
Vol 23 (suppl_1) ◽  
pp. e30-e30
Author(s):  
Maria Marano ◽  
Julia Orkin ◽  
Robin Hayeems ◽  
Stephen Meyn ◽  
Meaghan Snell ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Diagnostic Tool ◽  
Diagnostic Yield ◽  
Whole Genome ◽  
Complex Care ◽  
Genetic Condition ◽  
Children With Medical Complexity ◽  
Medical Complexity

Abstract BACKGROUND Genetic testing is often pursued in children with medical complexity (CMC), in an attempt to establish a unifying diagnosis, understand pathogenicity and disease progression, guide care and inform reproductive planning. CMC are defined by at least one chronic condition, technology dependence, multiple subspecialist involvement, and high healthcare utilization. Despite multiple efforts to confirm clinical suspicion of an underlying genetic condition, many remain undiagnosed. Whole genome sequencing (WGS) is becoming increasingly available as an informative diagnostic tool. The application of genomic technology to this population has the potential to increase the proportion of CMC for whom diagnoses are established, in an effort to reduce time and emotional burden of the diagnostic process, and reduce health care system costs. OBJECTIVES The main purpose of this study was to optimize the clinical implementation of state-of-the-art genome diagnostics for CMC, in terms of diagnostic yield. DESIGN/METHODS We conducted a prospective study using patients followed by the Complex Care program at a large urban tertiary care center. Research ethics board approval was obtained. Of 435 patients screened, 114 were eligible for inclusion as an underlying genetic condition was clinically suspected but not established to date by conventional genetic testing. To date, 21 participants were evaluated through a clinical genetic assessment, previous genetic testing review and peripheral blood-derived DNA sequence. A laboratory team identified candidate genetic variants associated with patients’ clinical symptoms, as well as other paediatric medically actionable variants. When found, these variants were validated as clinically significant by comparing the child’s DNA to his parents’. WGS diagnostic yield was then determined by calculating the proportion of cases for which a genetic diagnosis was established. RESULTS Of the 21 patients recruited, nine WGS analysis were completed thus far. Among these, four participants were diagnosed with established diseases, two of which were considered as novel diseases. One case was identified with a possible diagnosis, however, the interpretation of this clinical phenotype remains of unknown significance. The other four patients of the study remained undiagnosed. Given these preliminary results, the diagnostic yield of WGS was predicted at 44% in CMC. This can be compared to a previous study performed at our center in which the diagnostic rate for chromosomal microarray alone was reported to be 8% and microarray plus targeted gene sequencing 13%. CONCLUSION This study has shown WGS to be feasible and achieve a higher diagnostic yield in our complex care population. As detection rates improve and laboratory costs decrease overtime, WGS will undoubtedly become a more informative diagnostic tool, particularly in this population. Optimizing the application of this increasingly sophisticated genomic technology warrants further consideration.

The influence of age on the diagnostic yield of genetic testing in dilated cardiomyopathy

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D.E Cannie ◽  
A Protonotarios ◽  
M Lorenzini ◽  
M Akhtar ◽  
P Syrris ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Dilated Cardiomyopathy ◽  
Genetic Test ◽  
Diagnostic Yield ◽  
Young Patients ◽  
Positive Test ◽  
P Value ◽  
Study Cohort ◽  
Gene Encoding ◽  
Chi Square

Abstract Background Dilated cardiomyopathy (DCM) has an estimated population prevalence of 1/250 and is the underlying diagnosis in a third of heart failure patients. A substantial proportion of patients have familial disease caused by dominant mutations in one of more than 50 genes, but clinical practice guidelines recommend genetic testing in young patients with idiopathic DCM. There is an absence of robust data on the influence of age on the diagnostic yield of genetic testing. Methods The study cohort comprised 825 consecutive and unrelated patients (524 male (63.5%)) with DCM who underwent genetic testing from 2015 to 2019. Genetic variants were classified using American College of Medical Genetics (ACMG) criteria. Analyses were stratified by age and sex. Results 173 (20.1%) patients had a positive genetic test (“pathogenic” or “likely pathogenic” variant); 292 (34.4%) had a variant of unknown significance. Mean age at genetic testing was 49.9±14.4 years. Mean age of patients with a positive test was 47.6±13.6 years. 99 (18.9%) men and 67 (22.3%) women had a positive test (p=0.246). Mutations in the TTN gene, encoding for titin, accounted for 46.1% of positive results. 13.8% of mutations were in DSP, 8.4% in RBM20, 6% in FLNC, 4.2% in LMNA, 3.6% in BAG3 and 3.6% in MYH7. There was a trend to declining yield with age (likelihood ratio chi-square p value = 0.047). The yield was 17.2% in the 56–65 year age group and 11.5% above 66 years of age (figure 1). Conclusions Approximately 1 in 5 patients with DCM had a positive genetic test. The yield declined in patients over 66 years but remained above 11%, suggesting that genetic testing should not be confined to younger patients with DCM. Figure 1. Yield of Genetic Testing by Age Funding Acknowledgement Type of funding source: None

scholarly journals Whole genome sequencing in oncology: using scenario drafting to explore future developments

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Michiel van de Ven ◽  
Martijn J. H. G. Simons ◽  
Hendrik Koffijberg ◽  
Manuela A. Joore ◽  
Maarten J. IJzerman ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Clinical Utility ◽  
Turnaround Time ◽  
Barriers And Facilitators ◽  
Strategic Decision ◽  
Molecular Diagnostic ◽  
Whole Genome ◽  
Future Developments ◽  
Clinical Diagnostic

Abstract Background In oncology, Whole Genome Sequencing (WGS) is not yet widely implemented due to uncertainties such as the required infrastructure and expertise, costs and reimbursements, and unknown pan-cancer clinical utility. Therefore, this study aimed to investigate possible future developments facilitating or impeding the use of WGS as a molecular diagnostic in oncology through scenario drafting. Methods A four-step process was adopted for scenario drafting. First, the literature was searched for barriers and facilitators related to the implementation of WGS. Second, they were prioritized by international experts, and third, combined into coherent scenarios. Fourth, the scenarios were implemented in an online survey and their likelihood of taking place within 5 years was elicited from another group of experts. Based on the minimum, maximum, and most likely (mode) parameters, individual Program Evaluation and Review Technique (PERT) probability density functions were determined. Subsequently, individual opinions were aggregated by performing unweighted linear pooling, from which summary statistics were extracted and reported. Results Sixty-two unique barriers and facilitators were extracted from 70 articles. Price, clinical utility, and turnaround time of WGS were ranked as the most important aspects. Nine scenarios were developed and scored on likelihood by 18 experts. The scenario about introducing WGS as a clinical diagnostic with a lower price, shorter turnaround time, and improved degree of actionability, scored the highest likelihood (median: 68.3%). Scenarios with low likelihoods and strong consensus were about better treatment responses to more actionable targets (26.1%), and the effect of centralizing WGS (24.1%). Conclusions Based on current expert opinions, the implementation of WGS as a clinical diagnostic in oncology is heavily dependent on the price, clinical utility (both in terms of identifying actionable targets as in adding sufficient value in subsequent treatment), and turnaround time. These aspects and the optimal way of service provision are the main drivers for the implementation of WGS and should be focused on in further research. More knowledge regarding these factors is needed to inform strategic decision making regarding the implementation of WGS, which warrants support from all relevant stakeholders.

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