Despite no consensus on the definition of ‘seriousness’, the concept is regularly used in policy and practice contexts to categorise conditions, determine access to genetic technologies and uses of selective pregnancy termination. Whilst attempts have been made to create taxonomies of genetic condition seriousness to inform clinical and policy decision-making, these have often relied on condition appraisals made by health and genetics professionals. The views of people with genetic conditions have been largely under-represented. This study explores the concept of seriousness through the perspectives of people with a range of ‘clinically serious’ conditions (fragile X conditions, spinal muscular atrophy, cystic fibrosis, haemophilia, thalassaemia). Attitudes towards suffering, quality of life (QoL) and selective pregnancy termination were elucidated from 45 in-depth qualitative interviews and 469 postal/online surveys. The majority of participants reported good health/wellbeing, and the capacity for good QoL, despite experiencing suffering with their condition. Notably, participants with later-onset conditions held more negative views of their health and QoL, and were more likely to view their condition as an illness, than those with early-onset conditions. These participants were more likely to see their condition as part of their identity. Whilst most participants supported prenatal screening, there was little support for selective termination. Moreover, social environment emerged as a critical mediator of the experience of the condition. The complex and rich insights of people living with genetic conditions might usefully be incorporated into future genetic taxonomies of ‘seriousness’ to ensure they more accurately reflect the lived reality of those with genetic conditions.

As whole genome sequencing is being considered as a tool to deliver expanded newborn screening (NBS) globally, the range of equivocal results it could produce are gaining increased attention. For cystic fibrosis (CF) screening, the use of next generation sequencing within existing UK NBS programmes would increase the number of uncertain designations returned within results, including that of Cystic Fibrosis Screen Positive Inconclusive Diagnosis (CFSPID). However, the experiences of families already living with this designation have been under-explored. This study uses in-depth interviews to explore the perspectives of sixteen parents who received positive results from CF NBS, with varying degrees of prognostic un/certainty; parents with a child diagnosed with CF (n = 6), CF carrier status (n = 3) and those with the CFSPID designation (n = 7). The biographically disruptive nature of positive NBS results-regardless of immediate relevance to the child-dominated early experiences of positive results across all groups. For those with CF, biographical reparation involved becoming 'a CF family', underscoring biological kinship bonds and reinforcing familial identity. For those with uncertain results, biographical re-calibration was more complex. Diagnostic and prognostic uncertainty posed a barrier to entry for both the 'CF world' and the 'healthy kid' world, leading parents to attempt to minimise its role, either through rejection, or re-interpretation of their child's result. Other parents, however, experienced biographical reparation more dynamically. The concept of 'genetic nomadism' captures accounts of oscillation between the two worlds; movements that were responsive to evolving health experiences, as well as social, environmental and temporal factors. Through the concept of genetic nomadism, this paper delineates both the productive, as well as divisive, nature of uncertainty for biographical reparation in the aftermath of NBS, as well as the strategies parents use to harness it, in order to successfully navigate the world with a child with an ambiguous genetic future.

Background: In-person data collection has long been considered the ‘gold standard’ for qualitative data collection. Societal changes and the rapid increase in the use of remote methods during the Covid-19 pandemic intensified debate about the limitations and opportunities of remote data collection, while reigniting questions about data quality and inclusion. Objective: We sought to map available evidence exploring the characteristics and quality of remotely collected qualitative data compared to in-person qualitative data. Eligibility Criteria: A scoping review was conducted of empirical research studies that employed both remote and in-person methods with similar participants, to address the same research question. Sources of Evidence: Searches were conducted in MEDLINE, CINHAL, Web of Science, Scopus and Applied Social Science Index and Abstracts (ASSIA). The review includes peer reviewed articles published in English since 2000. Methods: Data were extracted from included papers using a data extraction tool based on JBI guidance, adapted to address our research questions. Results: A total of 58 articles are included. These cover a range of research methods and participant groups. Overall, remotely collected data is likely to generate similar themes to data collected in person but more concisely. Sensitive topics may be the exception. Non-verbal data and interaction between participants may be lost but the significance of this for data quality is not as well understood as participants may disclose more information remotely. Conclusions: Researchers should consider the fit of epistemology, population and topic when making decisions about remote data collection. If the benefits of remote data collection for qualitative research are to be fully realised, further research is needed to identify which elements of in-person and remote qualitative data collection are most effective, with which populations and research topics, and how remote data differs from in-person data.

Whole genome sequencing (WGS) is being considered as a tool to deliver newborn screening (NBS) internationally. Its use would dramatically increase the number of genetic variants identified, presenting a host of ethical, social, and practical considerations. A scoping review was conducted to examine the acceptability of WGS-NBS among parents, the public, and health professionals. Parent/public groups were enthusiastic about WGS-NBS, holding panoramic views of current/future benefits, incorporating family and wider society. While actionable early-onset findings were prioritized, non-actionable and uncertain results were still viewed as empowering. Conversely, professionals preferred selective results disclosure, prioritized by clinical need. They emphasized the need for meaningful consent and protection of the child’s autonomy. All groups outlined the importance of properly considered implementation (e.g. resources, governance) to minimize harms and prevent a reduction in NBS participation. As genomic medicine integrates into healthcare, divergent conceptualizations of “harms” and “benefits” across social groups must be considered.

Objective: To evaluate systematic review approaches to synthesising evidence for policy advisers who are considering whether to screen newborns for hundreds of rare diseases using whole genome sequencing. Design: Series of systematic reviews and roadmap for evidence generation for policy advisers. Data sources: Medline, Embase, Science Citation Index, Cochrane Library. Methods: 200 conditions included in Genomics England's Generation Study were stratified into five groups and one condition randomly selected from each group using criteria designed to maximise variability and availability of data. 30 systematic reviews were undertaken (five conditions, six review questions) about penetrance, detection rate, accuracy, benefit of earlier treatment, and benefits and harms of screening for the five conditions (search from inception to November 2023). Results were synthesised and reviewer time recorded. Genomic studies of newborn screening cohorts that reported penetrance were systematically reviewed using a non-condition specific approach (search inception to January 2024). The conditions and genes selected for reporting by these studies were identified. ClinGen was explored for synthesising evidence. All approaches were assessed by considering review effort and level and quality of evidence. Results: The five conditions selected for systematic review were pyridoxine dependent epilepsy, heritable retinoblastoma, X linked hypophosphataemic rickets, familial haemophagocytic lymphohistiocytosis, and medium chain acyl-CoA dehydrogenase deficiency. 19 689 titles were screened and 268 papers included that addressed two of six research questions (detection rate and treatment benefit). No studies were identified for the remaining four research questions. Total reviewer time for five conditions was seven months. A team of five reviewers would take over 20 years to conduct similar reviews for 200 conditions. 10 published genomic studies of newborn screening cohorts were identified with a total of 76 268 newborns. The number of conditions screened for varied from 74 to 903, with low concordance (two of 1453 genes were included in all 10 studies). Selection of conditions was primarily based on clinical opinion. All studies reported and acted on genetic findings considered clinically significant, preventing collection of penetrance data. Conclusions: Current evidence synthesis methods are neither feasible nor fruitful to provide policy advisers like the UK National Screening Committee with the evidence needed to understand the benefits and harms of newborn screening for multiple conditions using whole genome sequencing because the evidence is not available to synthesise. Evidence should be created through studies that only report pathogenic variants to parents and clinicians where penetrance and expressivity have been established through empirical evidence rather than clinical opinion. A roadmap for future evidence generation is proposed to highlight the need for new evidence generation combined with a staged approach to evaluation, focusing on pathogenic variants with evidence of high penetrance and expressivity. Registration: Review registration PROSPERO (CRD42023475529).

Background: Newborn screening using whole genome sequencing is being evaluated in numerous projects across the world, including Genomics England Limited’s Generation Study. It presents considerable challenges for policy advisors, not least, given the logistics of simultaneously evaluating the evidence for the suggested 200 rare genetic conditions. The ‘genotype-first’ approach has the potential for harms through overdiagnosis, and benefits are uncertain. Objective: To assess different approaches to evaluating whole genome sequencing for newborn screening to inform the development of a robust method of evaluation for informing policy decisions. Methods: We approached the objective with systematic review methods for a sample of five conditions (considering gene penetrance, expressivity, accuracy and effectiveness of whole genome sequencing and effect of earlier treatment) (search inception to November 2023), evaluated the National Institutes of Health [US] Clinical Genome Resource (ClinGen) as an alternative evidence source for the five conditions and we compared this to a review of genomic studies of newborn screening cohorts reporting penetrance for pathogenic variants of any paediatric condition (search inception to February 2024). We undertook a methodological review of economic evaluations of whole genome sequencing/whole exome sequencing (search inception to January 2024) and explored public views on evaluating whole genome sequencing. Data sources: MEDLINE (Ovid), EMBASE (Ovid), Web of Science, Science Citation Index (via Clarivate), the Cochrane Library (via Wiley), cost-effectiveness analysis registry and American Economic Association electronic bibliography. Actionability reports and scores from the Clinical Genome Resource website (downloaded 30 April 2024). Results: The traditional review approach identified 268 studies reporting the genetic spectrum of individuals with the five conditions or benefits of earlier, symptomatic treatment. No evidence on the penetrance and expressivity or the accuracy or effectiveness of whole genome sequencing in newborns was identified. A review of 200 conditions would take a team of five reviewers 23 years to complete. Clinical Genome Resource reviews were available for four or five conditions. All four ‘actionability’ ratings disagreed with the findings of our reviews. Our review of 14 genomic studies of newborn screening cohorts found insufficient information to allow individual highly penetrant pathogenic variants for any condition to be identified. None of the 86 economic evaluations of whole genome sequencing or whole exome sequencing were set in a screening context. Some micro-costing studies are available that could help understand the resource use and costs associated with whole genome sequencing. Following a series of patient and public involvement meetings, attendees appreciated the uncertainties of whole genome sequencing. A wider stakeholder perspective is needed to inform policy decisions. Limitations: Although we only examined five conditions in depth, the consistency in lack of data suggests that our conclusions are robust. Conclusions: The systematic review approach for evaluating whole genome sequencing of newborns identified a paucity of high-quality evidence. Extending the review to all 200 conditions is not feasible. Currently, the use of existing genome resources and review of genomic studies of newborn screening cohorts are not viable alternatives. The cost-effectiveness of whole genome sequencing in a newborn screening context is unknown. Future work: Large-scale collaborative research is required to evaluate the short- and long-term harms, benefits and economic implications of whole genome sequencing for screening newborns. We propose a staged approach to evaluation, considering only conditions with pathogenic variants with high penetrance to minimise harm from overdiagnosis. Study registration: This study is registered as PROSPERO CRD42023475529. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR159928) and is published in full in Health Technology Assessment ; Vol. 29, No. 65. See the NIHR Funding and Awards website for further award information.