Return of genetic testing results in the era of whole-genome sequencing

2015 ◽  
Vol 16 (9) ◽  
pp. 553-559 ◽  
Author(s):  
Bartha Maria Knoppers ◽  
Ma'n H. Zawati ◽  
Karine Sénécal
Keyword(s):  
Genetic Testing ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome

scholarly journals Continuing the sequence? Towards an economic evaluation of whole genome sequencing for the diagnosis of rare diseases in Scotland

2021 ◽  
Author(s):  
Michael Abbott ◽  
Lynda McKenzie ◽  
Blanca Viridiana Guizar Moran ◽  
Sebastian Heidenreich ◽  
Rodolfo Hernández ◽  
...  
Keyword(s):  
Economic Evaluation ◽  
Genetic Testing ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Diseases ◽  
Genomic Medicine ◽  
Future Research ◽  
Clinical Genetics ◽  
Whole Genome ◽  
Peace Of Mind

AbstractNovel developments in genomic medicine may reduce the length of the diagnostic odyssey for patients with rare diseases. Health providers must thus decide whether to offer genome sequencing for the diagnosis of rare conditions in a routine clinical setting. We estimated the costs of singleton standard genetic testing and trio-based whole genome sequencing (WGS), in the context of the Scottish Genomes Partnership (SGP) study. We also explored what users value about genomic sequencing. Insights from the costing and value assessments will inform a subsequent economic evaluation of genomic medicine in Scotland. An average cost of £1,841 per singleton was estimated for the standard genetic testing pathway, with significant variability between phenotypes. WGS cost £6625 per family trio, but this estimate reflects the use of WGS during the SGP project and large cost savings may be realised if sequencing was scaled up. Patients and families valued (i) the chance of receiving a diagnosis (and the peace of mind and closure that brings); (ii) the information provided by WGS (including implications for family planning and secondary findings); and (iii) contributions to future research. Our costings will be updated to address limitations of the current study for incorporation in budget impact modelling and cost-effectiveness analysis (cost per diagnostic yield). Our insights into the benefits of WGS will guide the development of a discrete choice experiment valuation study. This will inform a user-perspective cost–benefit analysis of genome-wide sequencing, accounting for the broader non-health outcomes. Taken together, our research will inform the long-term strategic development of NHS Scotland clinical genetics testing services, and will be of benefit to others seeking to undertake similar evaluations in different contexts.

scholarly journals A Family with a Novel Mutation and Polycythemia Vera

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4875-4875
Author(s):  
Mayra C. Robinson ◽  
Majd T Ghanim ◽  
Shayla Bergmann
Keyword(s):  
Bone Marrow ◽  
Genetic Testing ◽  
Whole Genome Sequencing ◽  
Polycythemia Vera ◽  
Genome Sequencing ◽  
Gene Mutations ◽  
Gene Sequencing ◽  
Janus Kinase ◽  
Whole Genome ◽  
Hematopoietic Stem

Abstract Background. Chronic myeloproliferative neoplasms are derived from myeloproliferation of a single hematopoietic stem cell and result in either erythrocythemia or thrombocytosis. Polycythemia Vera (PV) is defined by persistent proliferation of red cell mass in the peripheral blood and bone marrow with hemoglobin more than or equal to 16.5 gr/dL (49% Hematocrit) in males and 16 gr/dL (48% Hematocrit) in females. Around 98% of patients with PV harbor an acquired Janus Kinase 2 mutation, namely JAK2V617F. Other well described mutations in PV patients include the EPOR gene, Hypoxia-inducible factor 2 alpha (HIF2A) gene, PHD2 gene mutations and the rare Hemoglobin Tarrant. These mutations and other identified predisposing gene variants have all accounted for familial cases of PV. Presence of specific mutations can be associated with increased risk of myelodysplastic syndrome, progression of disease, and neoplasms which causes a decreased overall survival. Methods: We reviewed the charts and collected clinical information of 3 generations of one family with erythrocythemia, including PV diagnostic testing. Results: The proband, a 3-year-old female, presented to our clinic at 6 months of age with a hemoglobin of 16 gr/dL (upper limit of normal for age is 12.5 gr/dL). Family consisted of 3 generations of related females (maternal grandmother, mother and daughter) with the clinical characteristics of PV as described above, requiring frequent phlebotomy. Genetic testing, for known PV mutations, on the proband revealed no identifiable mutations, similar to the mother's and grandmother's prior genetic testing. The proband had no other laboratory abnormalities, and a bone marrow biopsy and aspirate examination was normal. Now 3 years of age, she has been undergoing phlebotomy every 3 months since diagnosis; further testing with exome gene sequencing showed c.136G>A mutation on EPO gene, a variant of unknown significance. Discussion. Literature review showed 2 previous reports of c.136G>A mutation in the EPO gene. In 2015, Taylor et al described the mutation in two families with erythrocytosis. Their project was aimed at evaluating whole-genome sequencing for diagnosis of families with high suspicion of a genetic component to their clinical presentation with no previously identified pathogenic variants. They concluded that c.136G>A is of autosomal dominant inheritance. Later described in 2016 by Camps et al., the variant was also found in 4 different non-related patients after whole genome sequencing. None of the previous citations demonstrated causality. Determination of predisposing gene mutations, using exome gene sequencing specifically for families with an unknown mutation may help clinicians with prognosis, genetic counseling, and possibly specific treatments. Although an interesting result, a causality between the variant identified and the patient in this report has not yet been verified. Therefore, more testing and reports of this mutation are needed. Further steps in our case will include whole exome sequencing of the proband's family members with idiopathic erythrocytosis to assess the presence of this variant in the whole family. Identification of a specific familial inherited gene mutation resulting in PV can help classify patients based on the mutation. This will help predict disease course, improve quality of life and determine risk of disease transformation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Know your genes. The marketing of direct-to-consumer genetic testing

2011 ◽  
Vol 10 (03) ◽  
pp. C01
Author(s):  
Alessandro Delfanti
Keyword(s):  
Genetic Testing ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Free Market ◽  
Public Communication ◽  
Genetic Mutations ◽  
Whole Genome ◽  
Life Choices ◽  
Private Companies ◽  
Direct To Consumer

Genetic testing promises to put the ability to decide about our life choices in our hands, as well as help solve crucial health problems by preventing the insurgence of diseases. But what happens when these exams are managed by private companies in a free market? Public communication and marketing have proven to be crucial battlefields on which companies companies need to engage in order to emerge. This issue of JCOM tries to shed some light on the communication and marketing practices used by private companies that sell direct-to-consumer genetic testing, from single genetic mutations to whole genome sequencing.

scholarly journals Whole Genome Sequencing Improves Outcomes of Genetic Testing in Patients With Hypertrophic Cardiomyopathy

2018 ◽  
Vol 72 (4) ◽  
pp. 419-429 ◽  
Author(s):  
Richard D. Bagnall ◽  
Jodie Ingles ◽  
Marcel E. Dinger ◽  
Mark J. Cowley ◽  
Samantha Barratt Ross ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Hypertrophic Cardiomyopathy ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome

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.

scholarly journals Low coverage whole genome sequencing enables accurate assessment of common variants and calculation of genome-wide polygenic scores

2019 ◽  
Author(s):  
Julian R. Homburger ◽  
Cynthia L. Neben ◽  
Gilad Mishne ◽  
Alicia Y. Zhou ◽  
Sekar Kathiresan ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Imputation Accuracy ◽  
Whole Genome ◽  
Genotyping Array ◽  
Pathogenic Variants ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Low Coverage

ABSTRACTBackgroundThe inherited susceptibility of common, complex diseases may be caused by rare, ‘monogenic’ pathogenic variants or by the cumulative effect of numerous common, ‘polygenic’ variants. As such, comprehensive genome interpretation could involve two distinct genetic testing technologies -- high coverage next generation sequencing for known genes to detect pathogenic variants and a genome-wide genotyping array followed by imputation to calculate genome-wide polygenic scores (GPSs). Here we assessed the feasibility and accuracy of using low coverage whole genome sequencing (lcWGS) as an alternative to genotyping arrays to calculate GPSs.MethodsFirst, we performed downsampling and imputation of WGS data from ten individuals to assess concordance with known genotypes. Second, we assessed the correlation between GPSs for three common diseases -- coronary artery disease (CAD), breast cancer (BC), and atrial fibrillation (AF) -- calculated using lcWGS and genotyping array in 184 samples. Third, we assessed concordance of lcWGS-based genotype calls and GPS calculation in 120 individuals with known genotypes, selected to reflect diverse ancestral backgrounds. Fourth, we assessed the relationship between GPSs calculated using lcWGS and disease phenotypes in 11,502 European individuals seeking genetic testing.ResultsWe found imputation accuracy r2 values of greater than 0.90 for all ten samples -- including those of African and Ashkenazi Jewish ancestry -- with lcWGS data at 0.5X. GPSs calculated using both lcWGS and genotyping array followed by imputation in 184 individuals were highly correlated for each of the three common diseases (r2 = 0.93 - 0.97) with similar score distributions. Using lcWGS data from 120 individuals of diverse ancestral backgrounds, including South Asian, East Asian, and Hispanic individuals, we found similar results with respect to imputation accuracy and GPS correlations. Finally, we calculated GPSs for CAD, BC, and AF using lcWGS in 11,502 European individuals, confirming odds ratios per standard deviation increment in GPSs ranging 1.28 to 1.59, consistent with previous studies.ConclusionsHere we show that lcWGS is an alternative approach to genotyping arrays for common genetic variant assessment and GPS calculation. lcWGS provides comparable imputation accuracy while also overcoming the ascertainment bias inherent to variant selection in genotyping array design.

Abstract 12075: Whole-Genome Sequencing at 10-Days of Life in Perinatal Long-QT Syndrome Yields New Insights Into Disease Pathogenesis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
James R Priest ◽  
Charles Gawad ◽  
Kris Kahlig ◽  
Scott Ceresnak ◽  
Lindsey Malloy-Walton ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Whole Genome Sequencing ◽  
Single Cell ◽  
Genome Sequencing ◽  
Molecular Diagnosis ◽  
Long Qt Syndrome ◽  
Whole Genome ◽  
Patch Clamping ◽  
Long Qt ◽  
Qt Syndrome

Introduction: Perinatal LQTS represents a severe form of long-QT syndrome with poor outcomes and early genotype-specific treatment is limited by the 2 month turnaround time of standard panel genetic testing. Hypothesis: We aimed to provide a molecular diagnosis within a clinically actionable timeframe. Methods: We performed rapid CLIA-certified whole genome sequencing on two infants with perinatal long-QT syndrome delivering a molecular diagnosis at 10-days of life. Whole cell patch clamping and single cell genotyping were also performed. Results: In Case #1 we discovered a previously characterized variant in KCNH2 which was paternally inherited, however whole genome sequencing provided an unbiased assessment of the entire catalog of human genes revealing a second maternally inherited modifier variant in RNF207. In Case #2 we discovered a novel mutation leucine replacing valine (V1762L) at residue 1762 in the SNC5A sodium channel. Whole-cell patch clamping experiments show the V1762L mutation causes a profound defect in late sodium current ~4.5 fold greater than the wild-type channel. A single cell analysis demonstrated that the mutation was present in the genome of only 3 of 36 individually isolated and genotyped patient cells, suggesting mosaicism. Conspicuously, standard panel genetic testing was negative. Conclusions: We report here the earliest molecular diagnoses of LQTS, and demonstrate that rapid whole genome sequencing may be fruitfully applied to perinatal LQTS. In case #1 we hypothesize that a polygenic inheritance may explain the early and severe perinatal presentation, and have identified a putative modifier gene for LQTS in RNF207. The observation of mosaicism in case #2 suggests that in studies of inherited disease, mosaicism represents a common mechanism by which causal variation may be missed.

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