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 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 MON-212 Genetic Spectrum Of A Canadian Cohort Of Sporadic Pheochromocytomas And Paragangliomas: Higher Prevalence Of Germline Mutations In PGL And NGS Assay With A Multigene Panel Increases The Mutation Rate

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Stefanie Parisien-La Salle ◽  
Nadine Dumas ◽  
Judith Jolin ◽  
Serge Nolet ◽  
André Lacroix ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Mutation Rate ◽  
Genetic Test ◽  
Germline Mutations ◽  
Canadian Population ◽  
Uncertain Significance ◽  
Exon 1 ◽  
High Heritability ◽  
Sanger Method ◽  
Multigene Panel

Abstract Background: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) (PPGLs) are rare tumors with a high heritability. The prevalence of germline mutations in sporadic PPGLs varies depending of series. Objective: To determine the prevalence and spectrum of germline mutations in our cohort of patients with apparently sporadic PPGLs. Method: We retrospectively reviewed the charts of patients with sporadic pathology-confirmed PPGLs who underwent genetic testing after genetic counselling at our Quaternary center from 2005–2019. Genetic analysis included sequential gene sequencing by Sanger method from 2005–2014 (n = 89) and a multigene sequencing by NGS with a panel (14 susceptibility genes for PPGLs) from 2015–2019 (n = 34). Some patients underwent both (n = 12). Results: Among 230 patients that were treated for PPGLs from 2005- 2019, 135 patients underwent genetic testing (77 females; 58 males and 77.8% French Canadians). There were 60 PGLs (29 head and neck, 21 abdominal and 10 thoracic) and 75 PHEOs, 4 being bilateral. The prevalence of pathogenic germline mutations was 27.4% (37/135). Patients carrying a germline mutation were younger than patients with no mutations (40.7 yo (20 - 67) vs. 49.6 yo (11 - 80)) and had a higher prevalence of metastatic tumors (26.6% vs. 20.4%). The prevalence of germline mutations was 43.3% (26/60) in PGLs and 14.7% (11/75) in PHEOs. In the 26 mutated PGLs, there were 13 SDHC (50.0%), 6 SDHB (23.1%), 4 SDHD (15.4%), 2 SDHA (7.7%) and 1 FH (3.8%) mutations. The recurrent pathogenic SDHC c.397C&gt;T (p.Arg133*) mutation was found in 12 out of the 13 SDHC mutations reflecting the presence of a funder effect in the French Canadian population. In the 11 mutated PHEOs, there were 3 MAX (27.3%), 3 VHL (27.3%), 2 RET (18.2%), 1 SDHB (9.1%), 1 NF1 (9.1%), 1 FH (9.1%) mutations. From 2015- 2019, we proposed NGS assay with the multigene panel to 12 patients (9 PHEOS and 3 PGLs) for whom the initial genetic test was negative. Novel germline mutations were found in 4 (33.3%) of these patients, representing 10.8% (4/37) of the mutation-carriers. Mutations were found in 2/9 PHEOs; a 28 yo female with bilateral PHEOs (MAX (deletion exon 1 and 2)) and a 33 yo male with malignant PHEO (MAX (c.3G&gt;A)), and in 2/3 PGLs; a 31 yo woman with metastatic abdominal PGL (SDHA (c.985C&gt;T) and a 59 yo woman with a thoracic PGL (SDHA (c.1432_1432 + 1del). Variants of uncertain significance (VUS) were identified in 7/60 PGLs (11.6%) and 5/75 PHEOs (6.7%) but the significance of these variants remains to be determined. Conclusion: In our cohort, the prevalence of germline mutations was of 44.3% in apparently sporadic PGLs and 14.7% in PHEOs. Genetic re-evaluation overtime using multigene sequencing by NGS assay in a subgroup of patients led to an increase of mutation rate in PHEOs and PGLs with the identification of germline MAX and SDHA mutations.

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 Assessing the readiness of precision medicine interoperabilty: An exploratory study of the National Institutes of Health genetic testing registry

2017 ◽  
Vol 24 (4) ◽  
pp. 323 ◽  
Author(s):  
Jay G Ronquillo ◽  
Chunhua Weng ◽  
William T Lester
Keyword(s):  
Genetic Testing ◽  
Precision Medicine ◽  
Healthcare Providers ◽  
National Institutes Of Health ◽  
Snomed Ct ◽  
Genetic Tests ◽  
Test Characteristics ◽  
Current State ◽  
Starting Point ◽  
Systematized Nomenclature Of Medicine

Background:  Precision medicine involves three major innovations currently taking place in healthcare:  electronic health records, genomics, and big data.  A major challenge for healthcare providers, however, is understanding the readiness for practical application of initiatives like precision medicine.Objective:  To better understand the current state and challenges of precision medicine interoperability using a national genetic testing registry as a starting point, placed in the context of established interoperability formats.Methods:  We performed an exploratory analysis of the National Institutes of Health Genetic Testing Registry.  Relevant standards included Health Level Seven International Version 3 Implementation Guide for Family History, the Human Genome Organization Gene Nomenclature Committee (HGNC) database, and Systematized Nomenclature of Medicine – Clinical Terms (SNOMED CT).  We analyzed the distribution of genetic testing laboratories, genetic test characteristics, and standardized genome/clinical code mappings, stratified by laboratory setting.Results: There were a total of 25472 genetic tests from 240 laboratories testing for approximately 3632 distinct genes.  Most tests focused on diagnosis, mutation confirmation, and/or risk assessment of germline mutations that could be passed to offspring.  Genes were successfully mapped to all HGNC identifiers, but less than half of tests mapped to SNOMED CT codes, highlighting significant gaps when linking genetic tests to standardized clinical codes that explain the medical motivations behind test ordering.  Conclusion:  While precision medicine could potentially transform healthcare, successful practical and clinical application will first require the comprehensive and responsible adoption of interoperable standards, terminologies, and formats across all aspects of the precision medicine pipeline.

scholarly journals Diagnostic yield of genetic tests in epilepsy

Neurology ◽  
2019 ◽  
Vol 92 (5) ◽  
pp. e418-e428 ◽  
Author(s):  
Iván Sánchez Fernández ◽  
Tobias Loddenkemper ◽  
Marina Gaínza-Lein ◽  
Beth Rosen Sheidley ◽  
Annapurna Poduri
Keyword(s):  
Genetic Testing ◽  
Cost Effectiveness ◽  
Publication Bias ◽  
Diagnostic Yield ◽  
Cost Effective ◽  
Effective Strategy ◽  
Genetic Tests ◽  
Cost Effective Strategy ◽  
Testing Strategies ◽  
The Cost

ObjectiveTo compare the cost-effectiveness of genetic testing strategies in patients with epilepsy of unknown etiology.MethodsThis meta-analysis and cost-effectiveness study compared strategies involving 3 genetic tests: chromosomal microarray (CMA), epilepsy panel (EP) with deletion/duplication testing, and whole-exome sequencing (WES) in a cost-effectiveness model, using “no genetic testing” as a point of comparison.ResultsTwenty studies provided information on the diagnostic yield of CMA (8 studies), EP (9 studies), and WES (6 studies). The diagnostic yield was highest for WES: 0.45 (95% confidence interval [CI]: 0.33–0.57) (0.32 [95% CI: 0.22–0.44] adjusting for potential publication bias), followed by EP: 0.23 (95% CI: 0.18–0.29), and CMA: 0.08 (95% CI: 0.06–0.12). The most cost-effective test was WES with an incremental cost-effectiveness ratio (ICER) of $15,000/diagnosis. However, after adjusting for potential publication bias, the most cost-effective test was EP (ICER: $15,848/diagnosis) followed by WES (ICER: $34,500/diagnosis). Among combination strategies, the most cost-effective strategy was WES, then if nondiagnostic, EP, then if nondiagnostic, CMA (ICER: $15,336/diagnosis), although adjusting for potential publication bias, the most cost-effective strategy was EP ± CMA ± WES (ICER: $18,385/diagnosis). While the cost-effectiveness of individual tests and testing strategies overlapped, CMA was consistently less cost-effective than WES and EP.ConclusionWES and EP are the most cost-effective genetic tests for epilepsy. Our analyses support, for a broad population of patients with unexplained epilepsy, starting with these tests. Although less expensive, CMA has lower yield, and its use as the first-tier test is thus not supported from a cost-effectiveness perspective.

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 Diagnostic Yield of Genetic Testing in Sudden Cardiac Death with Autopsy Findings of Uncertain Significance

2021 ◽  
Vol 10 (9) ◽  
pp. 1806
Author(s):  
Mercedes Iglesias ◽  
Tomas Ripoll-Vera ◽  
Consuelo Perez-Luengo ◽  
Ana Belen García ◽  
Susana Moyano ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Ventricular Hypertrophy ◽  
Diagnostic Yield ◽  
Left Ventricular ◽  
Molecular Autopsy ◽  
Variants Of Unknown Significance ◽  
Pathogenic Variants ◽  
Unknown Significance ◽  
Uncertain Significance ◽  
Frequent Variant

Background: Sudden death (SD) in the young usually has an underlying genetic cause. In many cases, autopsy reveals unspecific and inconclusive results, like idiopathic left ventricular hypertrophy (LVH), nonsignificant coronary atherosclerosis (CA), and primary myocardial fibrosis (PMF). Their pathogenicity and their relation to SD cause is unknown. This study aims to evaluate the diagnostic yield of genetic testing in these cases. Methods: SD cases, between 1 and 50 years old, with findings of uncertain significance (idiopathic LVH, nonsignificant CA and PMF) on autopsy were evaluated prospectively, including information about medical and family history and circumstances of death. Genetic testing was performed. Results: In a series of 195 SD cases, we selected 31 cases presenting idiopathic LVH (n = 16, 51.61%), nonsignificant CA (n = 17, 54.84%), and/or PMF (n = 24, 77.42%) in the autopsy. Mean age was 41 ± 7.2 years. Diagnostic yield of genetic test was 67.74%, considering variants of unknown significance (VUS), pathogenic variants (PV) and likely pathogenic variants (LPV); 6.45% including only PV and LPV. Structural genes represented 41,93% (n = 13) of cases, while 38,7% (n = 12) were related to channelopathies. Conclusion: Molecular autopsy in SD cases between 1 and 50 years old, with findings of uncertain significance, has a low diagnostic yield, being VUS the most frequent variant observed.

scholarly journals MAPS: machine-assisted phenotype scoring enables rapid functional assessment of genetic variants by high-content microscopy

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jesse T. Chao ◽  
Calvin D. Roskelley ◽  
Christopher J. R. Loewen
Keyword(s):  
Deep Learning ◽  
Genetic Testing ◽  
Cost Effective ◽  
Hereditary Diseases ◽  
Imaging Data ◽  
Loss Of Function ◽  
Experimental Conditions ◽  
Key Indicator ◽  
Uncertain Significance ◽  
Model Training

Abstract Background Genetic testing is widely used in evaluating a patient’s predisposition to hereditary diseases. In the case of cancer, when a functionally impactful mutation (i.e. genetic variant) is identified in a disease-relevant gene, the patient is at elevated risk of developing a lesion in their lifetime. Unfortunately, as the rate and coverage of genetic testing has accelerated, our ability to assess the functional status of new variants has fallen behind. Therefore, there is an urgent need for more practical, streamlined and cost-effective methods for classifying variants. Results To directly address this issue, we designed a new approach that uses alterations in protein subcellular localization as a key indicator of loss of function. Thus, new variants can be rapidly functionalized using high-content microscopy (HCM). To facilitate the analysis of the large amounts of imaging data, we developed a new software toolkit, named MAPS for machine-assisted phenotype scoring, that utilizes deep learning to extract and classify cell-level features. MAPS helps users leverage cloud-based deep learning services that are easy to train and deploy to fit their specific experimental conditions. Model training is code-free and can be done with limited training images. Thus, MAPS allows cell biologists to easily incorporate deep learning into their image analysis pipeline. We demonstrated an effective variant functionalization workflow that integrates HCM and MAPS to assess missense variants of PTEN, a tumor suppressor that is frequently mutated in hereditary and somatic cancers. Conclusions This paper presents a new way to rapidly assess variant function using cloud deep learning. Since most tumor suppressors have well-defined subcellular localizations, our approach could be widely applied to functionalize variants of uncertain significance and help improve the utility of genetic testing.

Parallel Computing for Tire Simulations

2011 ◽  
Vol 39 (3) ◽  
pp. 193-209 ◽  
Author(s):  
H. Surendranath ◽  
M. Dunbar
Keyword(s):  
High Performance ◽  
Effective Means ◽  
Cost Effective ◽  
Turnaround Time ◽  
Careful Consideration ◽  
Rolling Contact ◽  
Element Analysis ◽  
Parallel Solvers ◽  
Design Changes ◽  
Highly Nonlinear

Abstract Over the last few decades, finite element analysis has become an integral part of the overall tire design process. Engineers need to perform a number of different simulations to evaluate new designs and study the effect of proposed design changes. However, tires pose formidable simulation challenges due to the presence of highly nonlinear rubber compounds, embedded reinforcements, complex tread geometries, rolling contact, and large deformations. Accurate simulation requires careful consideration of these factors, resulting in the extensive turnaround time, often times prolonging the design cycle. Therefore, it is extremely critical to explore means to reduce the turnaround time while producing reliable results. Compute clusters have recently become a cost effective means to perform high performance computing (HPC). Distributed memory parallel solvers designed to take advantage of compute clusters have become increasingly popular. In this paper, we examine the use of HPC for various tire simulations and demonstrate how it can significantly reduce simulation turnaround time. Abaqus/Standard is used for routine tire simulations like footprint and steady state rolling. Abaqus/Explicit is used for transient rolling and hydroplaning simulations. The run times and scaling data corresponding to models of various sizes and complexity are presented.

scholarly journals Current and Future Pathotyping Platforms for Plasmodiophora brassicae in Canada

Plants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1446
Author(s):  
Heather H. Tso ◽  
Leonardo Galindo-González ◽  
Stephen E. Strelkov
Keyword(s):  
Crop Production ◽  
Plasmodiophora Brassicae ◽  
Cost Effective ◽  
Turnaround Time ◽  
Molecular Techniques ◽  
Differential Set ◽  
Management Plans ◽  
Increased Sensitivity ◽  
Phenotypic Methods ◽  
Important Disease

Clubroot, caused by Plasmodiophora brassicae, is one of the most detrimental threats to crucifers worldwide and has emerged as an important disease of canola (Brassica napus) in Canada. At present, pathotypes are distinguished phenotypically by their virulence patterns on host differential sets, including the systems of Williams, Somé et al., the European Clubroot Differential set, and most recently the Canadian Clubroot Differential set and the Sinitic Clubroot Differential set. Although these are frequently used because of their simplicity of application, they are time-consuming, labor-intensive, and can lack sensitivity. Early, preventative pathotype detection is imperative to maximize productivity and promote sustainable crop production. The decreased turnaround time and increased sensitivity and specificity of genotypic pathotyping will be valuable for the development of integrated clubroot management plans, and interest in molecular techniques to complement phenotypic methods is increasing. This review provides a synopsis of current and future molecular pathotyping platforms for P. brassicae and aims to provide information on techniques that may be most suitable for the development of rapid, reliable, and cost-effective pathotyping assays.

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