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 The Brazilian Rare Genomes Project: validation of whole genome sequencing for rare diseases diagnosis

2021 ◽  
Author(s):  
Antonio Victor Campos Coelho ◽  
Bruna Mascaro Cordeiro de Azevedo ◽  
Danielle Ribeiro Lucon ◽  
Maria Soares Nobrega ◽  
Rodrigo de Souza Reis ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Diseases ◽  
Clinical Laboratory ◽  
Genomic Medicine ◽  
Uniparental Disomy ◽  
Public Healthcare ◽  
Whole Genome ◽  
Single Nucleotide Variants ◽  
F Measure

Rare diseases affect 3.2 to 13.2 million individuals in Brazil. The Brazilian Rare Genomes Project is envisioned to further the implementation of genomic medicine into the Brazilian public healthcare system. Here we report the results of the validation of a whole genome sequencing (WGS) procedure for implementation in a clinical laboratory. In addition, we report data quality for the first 1,200 real world patients sequenced. For the validation, we sequenced a well characterized group of 76 samples, including seven gold standard genomes, using a PCR-free WGS protocol on Illumina Novaseq 6000 equipment. We compared the observed variant calls with their expected calls, observing good concordance for single nucleotide variants (SNVs; mean F-measure = 99.82%) and indels (mean F-measure = 99.57%). Copy number variants and structural variants events detection performances were as expected (F-measures 96.6% and 90.3%, respectively). Our protocol presented excellent intra- and inter-assay reproducibility, with coefficients of variation ranging between 0.03% and 0.20% and 0.02% and 0.09%, respectively. Limitations of the procedure include the inability to confidently detect variants such as uniparental disomy, balanced translocations, repeat expansion variants and low-level mosaicism. In summary, the observed performance of the test was in accordance with that seen in the best centers worldwide. The Rare Genomes Project is an important initiative to improve Brazil's general population access to the innovative WGS technology which has the potential to reduce the time until diagnosis of rare diseases, bringing pivotal improvements for the quality of life of the affected individuals.

scholarly journals Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Henrik Stranneheim ◽  
Kristina Lagerstedt-Robinson ◽  
Måns Magnusson ◽  
Malin Kvarnung ◽  
Daniel Nilsson ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Diseases ◽  
De Novo ◽  
Genomic Medicine ◽  
Uniparental Disomy ◽  
Healthcare Setting ◽  
University Hospital ◽  
Whole Genome ◽  
Number Of Patients

Abstract Background We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital and Science for Life Laboratory to establish advanced, genomics-based diagnostics in the Stockholm healthcare setting. Methods Our analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualization of results for clinical interpretation is carried out in Scout—a custom-developed decision support system. Results from both singleton (84%) and trio/family (16%) analyses are reported. Variant interpretation is done by 15 expert teams at the hospital involving staff from three clinics. For patients with complex phenotypes, data is shared between the teams. Results Overall, 40% of the patients received a molecular diagnosis ranging from 19 to 54% for specific disease groups. There was heterogeneity regarding causative genes (n = 754) with some of the most common ones being COL2A1 (n = 12; skeletal dysplasia), SCN1A (n = 8; epilepsy), and TNFRSF13B (n = 4; inborn errors of immunity). Some causative variants were recurrent, including previously known founder mutations, some novel mutations, and recurrent de novo mutations. Overall, GMCK-RD has resulted in a large number of patients receiving specific molecular diagnoses. Furthermore, negative cases have been included in research studies that have resulted in the discovery of 17 published, novel disease-causing genes. To facilitate the discovery of new disease genes, GMCK-RD has joined international data sharing initiatives, including ClinVar, UDNI, Beacon, and MatchMaker Exchange. Conclusions Clinical WGS at GMCK-RD has provided molecular diagnoses to over 1200 individuals with a broad range of rare diseases. Consolidation and spread of this clinical-academic partnership will enable large-scale national collaboration.

scholarly journals Identifying Aspects of Public Attitudes Toward Whole Genome Sequencing to Inform the Integration of Genomics into Care

2021 ◽  
pp. 1-12
Author(s):  
Holly Etchegary ◽  
Daryl Pullman ◽  
Charlene Simmonds ◽  
Zoha Rabie ◽  
Proton Rahman
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Online Survey ◽  
Public Attitudes ◽  
Genetic Counselor ◽  
Genomic Medicine ◽  
Genomic Data ◽  
Whole Genome ◽  
The Public ◽  
Genomic Test

<b><i>Introduction:</i></b> The growth of global sequencing initiatives and commercial genomic test offerings suggests the public will increasingly be confronted with decisions about sequencing. Understanding public attitudes can assist efforts to integrate sequencing into care and inform the development of public education and outreach strategies. <b><i>Methods:</i></b> A 48-item online survey was advertised on Facebook in Eastern Canada and hosted on SurveyMonkey in late 2018. The survey measured public interest in whole genome sequencing and attitudes toward various aspects of sequencing using vignettes, scaled, and open-ended items. <b><i>Results:</i></b> While interest in sequencing was high, critical attitudes were observed. In particular, items measuring features of patient control and choice regarding genomic data were strongly endorsed by respondents. Majority wanted to specify upfront how their data could be used, retain the ability to withdraw their sample at a later date, sign a written consent form, and speak to a genetic counselor prior to sequencing. Concerns about privacy and unauthorized access to data were frequently observed. Education level was the sociodemographic variable most often related to attitude statements such that those with higher levels of education generally displayed more critical attitudes. <b><i>Conclusions:</i></b> Attitudes identified here could be used to inform the development of implementation strategies for genomic medicine. Findings suggest health systems must address patient concerns about privacy, consent practices, and the strong desire to control what happens to their genomic data through public outreach and education. Specific oversight procedures and policies that are clearly communicated to the public will be required.

scholarly journals 6 Translating genomics for clinical benefit

2019 ◽  
Vol 95 (1130) ◽  
pp. 686.3-686
Author(s):  
Mark Caulfield
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genomic Medicine ◽  
Health Gain ◽  
Annual Review ◽  
Whole Genome ◽  
Department Of Health ◽  
Data Points ◽  
Genome Analyses ◽  
The Uk

The UK 100,000 Genomes Project has focussed on transforming genomic medicine in the National Health Service using whole genome sequencing in rare disease, cancer and infection. Genomics England partnering with the NHS established 13 Genomic Medicine Centres, the NHS whole genome sequencing centre and the Genomics England Clinical Interpretation Partnership (3337 researchers from 24 countries). We sequenced the 100,000th genome on the 5th December 2019 and completed an initial analysis for participants in July 2019. Alongside these genomes we have assembled a longitudinal life course dataset for research and diagnosis including 2.6 billion clinical data points for the 3000 plus researchers to work on to drive up the value of the genomes for direct healthcare. In parallel we have partnered the NHS to establish one of the world’s most advanced Genomic Medicine Service where we re-evaluated 300,000 genomic tests and upgraded 25% of tests to newer technologies with an annual review. The Department of Health have announced the ambition to undertake 5 million genome analyses over the next 5 years focused on new areas tractable to health gain.

scholarly journals Linked-read whole-genome sequencing resolves common and private structural variants in multiple myeloma

2021 ◽  
Author(s):  
Lucía Peña Pérez ◽  
Nicolai Frengen ◽  
Julia Hauenstein ◽  
Charlotte Gran ◽  
Charlotte Gustafsson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cohort Analysis ◽  
Genomic Medicine ◽  
Molecular Classification ◽  
Regulatory Elements ◽  
Copy Number Variations ◽  
Whole Genome ◽  
Structural Variants

Multiple myeloma (MM) is an incurable and aggressive plasma cell malignancy characterized by a complex karyotype with multiple structural variants (SVs) and copy number variations (CNVs). Linked-read whole-genome sequencing (lrWGS) allows for refined detection and reconstruction of SVs by providing long-range genetic information from standard short-read sequencing. This makes lrWGS an attractive solution for capturing the full genomic complexity of MM. Here we show that high-quality lrWGS data can be generated from low numbers of FACS sorted cells without DNA purification. Using this protocol, we analyzed FACS sorted MM cells from 37 MM patients with lrWGS. We found high concordance between lrWGS and FISH for the detection of recurrent translocations and CNVs. Outside of the regions investigated by FISH, we identified >150 additional SVs and CNVs across the cohort. Analysis of the lrWGS data allowed for resolving the structure of diverse SVs affecting the MYC and t(11;14) loci causing the duplication of genes and gene regulatory elements. In addition, we identified private SVs causing the dysregulation of genes recurrently involved in translocations with the IGH locus and show that these can alter the molecular classification of the MM. Overall, we conclude that lrWGS allows for the detection of aberrations critical for MM prognostics and provides a feasible route for providing comprehensive genetics. Implementing lrWGS could provide more accurate clinical prognostics, facilitate genomic medicine initiatives, and greatly improve the stratification of patients included in clinical trials.

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.

Patients with PMD who are thoroughly screened by Genomic medicine have a considerable chance of benefiting greatly from whole-genome sequencing

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Direct Sequencing ◽  
Genomic Medicine ◽  
Diagnostic Process ◽  
Whole Genome ◽  
Rna Seq ◽  
Tissue Samples ◽  
Long Read ◽  
Major Transition

It appears that the role of genetics in neurology is undergoing a major transition in the present. The scope of genomic medicine has advanced from the only realm of academic investigation to the well-established and widely accepted instrument for genetic labs. Previously, this test was reserved for the most challenging patients, but today it is being utilized as a first step in looking at rare inherited neurological disorders. Researchers and clinicians working in the field of mitochondrial medicine will need to employ new laboratory techniques and DNA sequencing technology in order to move forward with future diagnosis methods and cut down on research time. Patients with PMD who are thoroughly screened have a considerable chance of benefiting greatly from whole-genome sequencing (WGS) at the beginning of their diagnostic process. Using long-read sequencing, there is the potential to help in the discovery of new genetic causes of PMD, the resolution of phasing issues, and the advancement of RNA and mtDNA investigations by way of direct sequencing. With the use of a great number of tissue samples from patients with PMD, there are significant advantages which can greatly promote the quick implementation of this technique into diagnostic laboratories. As RNA-seq technology is introduced into diagnostic laboratories, it will serve as an accurate means to examine the entire spectrum of disease while providing support for difficult cases. The plentiful supply of tissue samples from patients with PMD further enhances the ability of RNA-seq to rapidly be adopted in these laboratories. Finally, more validation of innovative tRNA approaches will be required in order to determine the pathogenicity of this common group of mtDNA-related PMDs.

Whole-genome sequencing as a first-tier diagnostic framework for rare genetic diseases

2021 ◽  
pp. 153537022110400
Author(s):  
Haseeb Nisar ◽  
Bilal Wajid ◽  
Samiah Shahid ◽  
Faria Anwar ◽  
Imran Wajid ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Diseases ◽  
Genetic Diseases ◽  
Correct Diagnosis ◽  
Clinical Settings ◽  
Whole Genome ◽  
Rare Genetic Diseases ◽  
Diagnostic Approaches ◽  
Diagnostic Framework

Rare diseases affect nearly 300 million people globally with most patients aged five or less. Traditional diagnostic approaches have provided much of the diagnosis; however, there are limitations. For instance, simply inadequate and untimely diagnosis adversely affects both the patient and their families. This review advocates the use of whole genome sequencing in clinical settings for diagnosis of rare genetic diseases by showcasing five case studies. These examples specifically describe the utilization of whole genome sequencing, which helped in providing relief to patients via correct diagnosis followed by use of precision medicine.

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