13 research outputs found
The implementation of large-scale genomic screening or diagnostic programmes: A rapid evidence review
Genomic healthcare programmes, both in a research and clinical context, have demonstrated a pivotal opportunity to prevent, diagnose, and treat rare diseases. However, implementation factors could increase overall costs and affect uptake. As well, uncertainties remain regarding effective training, guidelines and legislation. The purpose of this rapid evidence review was to draw together the available global evidence on the implementation of genomic testing programmes, particularly on population-based screening and diagnostic programmes implemented at the national level, to understand the range of factors influencing implementation. This review involved a search of terms related to genomics, implementation and health care. The search was limited to peer-reviewed articles published between 2017–2022 and found in five databases. The review included thirty articles drawing on sixteen countries. A wide range of factors was cited as critical to the successful implementation of genomics programmes. These included having policy frameworks, regulations, guidelines; clinical decision support tools; access to genetic counselling; and education and training for healthcare staff. The high costs of implementing and integrating genomics into healthcare were also often barriers to stakeholders. National genomics programmes are complex and require the generation of evidence and addressing implementation challenges. The findings from this review highlight that there is a strong emphasis on addressing genomic education and engagement among varied stakeholders, including the general public, policymakers, and governments. Articles also emphasised the development of appropriate policies and regulatory frameworks to govern genomic healthcare, with a focus on legislation that regulates the collection, storage, and sharing of personal genomic data
Written communication of whole genome sequencing results in the NHS Genomic Medicine Service: a multi-centre service evaluation
Whole genome sequencing (WGS) is being used in diagnostic testing for certain clinical indications within the NHS Genomic Medicine Service (GMS) in England. Letter writing is an integral part of delivering results. However, no national guidelines for writing results from WGS exist. This multi-centre service evaluation used mixed methods to understand the content and readability of letters returning diagnostic, variant of uncertain significance (VUS), and no-finding results to paediatric rare disease patients. Eight Regional Genetics Services (response rate 47%) in England provided a total of 37 letters returning diagnostic (n = 13), VUS (n = 10), and no-finding (n = 14) results. Diagnostic and VUS results were usually delivered during an appointment; no-finding results were typically delivered by letter only. Letters were diverse in which content topics they covered and level of detail. No-finding letters (14/14) explained the result but were less likely to cover other topics. Diagnostic letters discussed the result (13/13), the condition (13/13), clinical genetics follow-up (13/13), clinical management (10/13), and adapting to the result (9/13). VUS letters explained the result (10/10), diagnostic uncertainty (10/10), and clinical genetics follow-up (10/10). Uncertainty was a common component of letters (33/37), irrespective of the result. Reanalysis or review after one or more years was suggested in 6/13 diagnostic, 7/10 VUS, and 6/14 no-finding letters. The mean reading level of letters corresponded to 15–17 years. Understanding how WGS results are conveyed to families during appointments, as well as how families interpret that information, is needed to provide a more comprehensive overview of results communication and inform best practices
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Perceptions of genomic newborn screening: a cross-sectional survey conducted with UK medical students.
BACKGROUND: With the potential to identify a vast number of rare diseases soon after birth, genomic newborn screening (gNBS) could facilitate earlier interventions and improve health outcomes. Designing a gNBS programme will involve balancing stakeholders' opinions and addressing concerns. The views of medical students-future clinicians who would deliver gNBS-have not yet been explored. METHODS: We conducted a nationwide online survey of UK medical students via the REDCap platform. Perceptions of gNBS, including scope of testing and potential benefits and drawbacks, were explored using a mix of multiple-choice questions, Likert scales, visual analogue scales and free-text questions. RESULTS: In total, 116 medical students across 16 universities participated. Overall, 45% supported gNBS, with a positively skewed mean support score of 3.24 (SD 1.26, range: 1.0-5.0), and 55% felt it relevant to their future practice. Almost all agreed that infant-onset and childhood-onset diseases and conditions with effective treatments should be included. Most felt that earlier interventions and personalised care would be the most important benefit of gNBS. Other perceived benefits included earlier diagnoses, diagnosing more patients and enabling research for new treatments. However, several perceived challenges were highlighted: risk of genomic discrimination, incidental or uncertain findings, data security and breaching children's future autonomy. Students expressed conflicting opinions on the psychological impact on families, but most were concerned about a lack of support due to current resource limitations in health services. Students frequently reported having insufficient knowledge to form an opinion, which may reflect gaps in genomics education at medical school and the current lack of evidence base for gNBS. CONCLUSION: Although some support for gNBS was demonstrated, ethicolegal and social challenges were raised, emphasising a need for ongoing discussions about the implications of gNBS
Public and patient involvement in research to support genome services development in the UK
Public and patient involvement (PPI) - the collaboration in research with members of the public and patients with relevant experience - is becoming well established in health service research in the UK. It is supported by funders and academic institutions. Published principles and guidelines for researchers, developed through consultation and consensus building, are available. Meanwhile, as genome sequencing is adopted into routine health care, translational genomics research and research to evaluate new genomic services are growing. Given the ethical and social implications of offering genome sequencing within a national health service, it is important that researchers give full consideration to planning and implementing meaningful PPI. Here we present five case studies of PPI in a variety of clinical genomic studies, including commentary on positive impacts and suggestions for improvements. We call for funders and academic institutions to continue and increase their efforts to enable and promote PPI across genomic and other health service research
Newborn Screening by Genomic Sequencing: Opportunities and Challenges
Newborn screening for treatable disorders is one of the great public health success stories of the twentieth century worldwide. This commentary examines the potential use of a new technology, next generation sequencing, in newborn screening through the lens of the Wilson and Jungner criteria. Each of the ten criteria are examined to show how they might be applied by programmes using genomic sequencing as a screening tool. While there are obvious advantages to a method that can examine all disease-causing genes in a single assay at an ever-diminishing cost, implementation of genomic sequencing at scale presents numerous challenges, some which are intrinsic to screening for rare disease and some specifically linked to genomics-led screening. In addition to questions specific to routine screening considerations, the ethical, communication, data management, legal, and social implications of genomic screening programmes require consideration
A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project
BackgroundGenomic variants which disrupt splicing are a major cause of rare genetic diseases. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Improving the clinical interpretation of non-canonical splicing variants offers a major opportunity to uplift diagnostic yields from whole genome sequencing data.MethodsHere, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project and assess the contribution of non-canonical splicing variants to rare genetic diseases. We use a variant-level constraint metric (the mutability-adjusted proportion of singletons) to identify constrained functional variant classes near exon–intron junctions and at putative splicing branchpoints. To identify new diagnoses for individuals with unsolved rare diseases in the 100,000 Genomes Project, we identified individuals with de novo single-nucleotide variants near exon–intron boundaries and at putative splicing branchpoints in known disease genes. We identified candidate diagnostic variants through manual phenotype matching and confirmed new molecular diagnoses through clinical variant interpretation and functional RNA studies.ResultsWe show that near-splice positions and splicing branchpoints are highly constrained by purifying selection and harbour potentially damaging non-coding variants which are amenable to systematic analysis in sequencing data. From 258 de novo splicing variants in known rare disease genes, we identify 35 new likely diagnoses in probands with an unsolved rare disease. To date, we have confirmed a new diagnosis for six individuals, including four in whom RNA studies were performed.ConclusionsOverall, we demonstrate the clinical value of examining non-canonical splicing variants in individuals with unsolved rare diseases
A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project.
Funder: Wessex Medical ResearchFunder: Health Education EnglandFunder: Rosetrees TrustBACKGROUND: Genomic variants which disrupt splicing are a major cause of rare genetic diseases. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Improving the clinical interpretation of non-canonical splicing variants offers a major opportunity to uplift diagnostic yields from whole genome sequencing data. METHODS: Here, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project and assess the contribution of non-canonical splicing variants to rare genetic diseases. We use a variant-level constraint metric (the mutability-adjusted proportion of singletons) to identify constrained functional variant classes near exon-intron junctions and at putative splicing branchpoints. To identify new diagnoses for individuals with unsolved rare diseases in the 100,000 Genomes Project, we identified individuals with de novo single-nucleotide variants near exon-intron boundaries and at putative splicing branchpoints in known disease genes. We identified candidate diagnostic variants through manual phenotype matching and confirmed new molecular diagnoses through clinical variant interpretation and functional RNA studies. RESULTS: We show that near-splice positions and splicing branchpoints are highly constrained by purifying selection and harbour potentially damaging non-coding variants which are amenable to systematic analysis in sequencing data. From 258 de novo splicing variants in known rare disease genes, we identify 35 new likely diagnoses in probands with an unsolved rare disease. To date, we have confirmed a new diagnosis for six individuals, including four in whom RNA studies were performed. CONCLUSIONS: Overall, we demonstrate the clinical value of examining non-canonical splicing variants in individuals with unsolved rare diseases
A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project
Abstract Background Genomic variants which disrupt splicing are a major cause of rare genetic diseases. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Improving the clinical interpretation of non-canonical splicing variants offers a major opportunity to uplift diagnostic yields from whole genome sequencing data. Methods Here, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project and assess the contribution of non-canonical splicing variants to rare genetic diseases. We use a variant-level constraint metric (the mutability-adjusted proportion of singletons) to identify constrained functional variant classes near exon–intron junctions and at putative splicing branchpoints. To identify new diagnoses for individuals with unsolved rare diseases in the 100,000 Genomes Project, we identified individuals with de novo single-nucleotide variants near exon–intron boundaries and at putative splicing branchpoints in known disease genes. We identified candidate diagnostic variants through manual phenotype matching and confirmed new molecular diagnoses through clinical variant interpretation and functional RNA studies. Results We show that near-splice positions and splicing branchpoints are highly constrained by purifying selection and harbour potentially damaging non-coding variants which are amenable to systematic analysis in sequencing data. From 258 de novo splicing variants in known rare disease genes, we identify 35 new likely diagnoses in probands with an unsolved rare disease. To date, we have confirmed a new diagnosis for six individuals, including four in whom RNA studies were performed. Conclusions Overall, we demonstrate the clinical value of examining non-canonical splicing variants in individuals with unsolved rare diseases.</span