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Rare disease genomic testing in the UK and Ireland: promoting timely and equitable access.
PURPOSE AND SCOPE: The aim of this position statement is to provide recommendations regarding the delivery of genomic testing to patients with rare disease in the UK and Ireland. The statement has been developed to facilitate timely and equitable access to genomic testing with reporting of results within commissioned turnaround times. METHODS OF STATEMENT DEVELOPMENT: A 1-day workshop was convened by the UK Association for Clinical Genomic Science and attended by key stakeholders within the NHS Genomic Medicine Service, including clinical scientists, clinical geneticists and patient support group representatives. The aim was to identify best practice and innovations for streamlined, geographically consistent services delivering timely results. Attendees and senior responsible officers for genomic testing services in the UK nations and Ireland were invited to contribute. RESULTS AND CONCLUSIONS: We identified eight fundamental requirements and describe these together with key enablers in the form of specific recommendations. These relate to laboratory practice (proportionate variant analysis, bioinformatics pipelines, multidisciplinary team working model and test request monitoring), compliance with national guidance (variant classification, incidental findings, reporting and reanalysis), service development and improvement (multimodal testing and innovation through research, informed by patient experience), service demand, capacity management, workforce (recruitment, retention and development), and education and training for service users. This position statement was developed to provide best practice guidance for the specialist genomics workforce within the UK and Ireland but is relevant to any publicly funded healthcare system seeking to deliver timely rare disease genomic testing in the context of high demand and limited resources.
Equity and timeliness as factors in the effectiveness of an ethical prenatal sequencing service: reflections from parents and professionals.
Prenatal sequencing tests are being introduced into clinical practice in many developed countries. In part due to its greater ability to detect genetic variation, offering prenatal sequencing can present ethical challenges. Here we review ethical issues arising following the implementation of prenatal sequencing in the English National Health Service (NHS). We analysed semi structured interviews conducted with 48 parents offered prenatal sequencing and 63 health professionals involved in delivering the service to identify the ethical issues raised. Two main themes were identified: (1) Equity of access (including issues around eligibility criteria, laboratory analytical processes, awareness and education of clinicians, fear of litigation, geography, parental travel costs, and access to private healthcare), and (2) Timeliness and its impact on parental decision-making in pregnancy (in the context of the law around termination of pregnancy, decision-making in the absence of prenatal sequencing results, and the "importance" of prenatal sequencing results). Recognising both the practical and systemic ethical issues that arise out of delivering a national prenatal sequencing service is crucial. Although specific to the English context, many of the issues we identified are applicable to prenatal sequencing services more broadly. Education of health professionals and parents will help to mitigate some of these ethical issues.
What is the role of bioethics in the face of persistent ethical disagreement?
Tuesday, 26 November 2024, 2pm to 5pm
Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus.
Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.
Bioethics and the value of disagreement.
What does it mean to be a bioethicist? How should the role(s) of bioethics be understood in the context of a world of intense value conflict and polarisation? Bioethics is-in all its various forms and traditions-potentially well-positioned to contribute to addressing many of the most pressing challenges of value polarisation and conflict in diverse societies. However, realising this potential is going to require moving beyond currently foregrounded methods and developing new models for engaging with moral disagreement. This paper proposes an approach, 'adversarial cooperation,' drawing on the concepts of 'adversarial collaboration' from the sciences and 'antagonistic cooperation' from the humanities. Adversarial cooperation aims to combine the rigour and structured methodology of adversarial collaboration with the cultural sensitivity and expansive vision of antagonistic cooperation. The paper also addresses key challenges to adversarial cooperation, including ethical considerations, tensions between substantive and procedural values, the problem of misinformation and the need for decision-making amidst ongoing disagreement. Ultimately, adversarial cooperation suggests a reimagining of bioethical expertise, emphasising skills in mediation, the arts and humanities and participatory decision-making alongside established philosophical competencies. This implies a model of normative bioethical authority grounded in the ability to facilitate inclusive and trustworthy processes of moral deliberation. Realising the potential of adversarial cooperation will require significant changes in bioethics training and practice, as well as a commitment to reflexivity, humility and the amplification of marginalised voices. By embracing this approach, bioethics can play a vital role in navigating the complex moral landscapes of pluralistic societies.
Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.
While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.
Global health photography behind the façade of empowerment and decolonisation.
Global health photography has historically been commissioned and, therefore, dominated by the gaze of Western photographers on assignments in the Global South. This is changing as part of international calls to decolonise global health and stimulate 'empowerment', spawning a growing initiative to hire local photographers. This article, based on interviews with global health photographers, reflects on this paradigm shift. It highlights how behind the laudable aim of 'empowerment' of local global health photography there is a simultaneous exploitation of precarious photographer labour and the emergence of 'glocal' photography elites. The paper argues that empowerment of local photographers can become a euphemism for reducing image production costs and maintaining control over the image content, while extending the scope of mainstream global health visual culture without challenging it. Finally, the article amplifies the growing concern that uncritical engagement with institutionalised empowerment becomes a warrant for the reproduction of local inequalities behind the fashionable façade of cooperation and care.