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Genome sequencing (GS) will have a profound impact on the diagnosis of rare and inherited diseases in children and young people. We conducted 27 semi-structured interviews with young people aged 11-19 having GS through the UK 100, 000 Genomes Project. Participants demonstrated an understanding of the role and function of genes and DNA, however the terms 'genome' and 'genome sequencing' were less well understood. Participants were primarily motivated to take part to get a diagnosis or identify the gene causing their condition. The majority of participants understood they might not receive a diagnostic result. Most were unconcerned about data security or access, however anxieties existed around what the results might show and the potential for disappointment if the result was negative. Signing an assent form empowered young people, formalised the process and instilled a sense of responsibility for their choice to participate. Most young people (≥16 years) had consented to receive secondary findings and had come to that decision without parental influence. Our research suggests that at least some young people are capable of making informed decisions about taking part in GS, and that involving them in discussions about testing can empower them to take responsibility over healthcare decisions that affect them., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Rapid genomic sequencing (RGS) is increasingly being used in the care of critically ill children. Here we describe a qualitative study exploring parent and professional perspectives around the usefulness of this test, the potential for unintended harms and the challenges for delivering a wider clinical service. The Rapid Paediatric Sequencing (RaPS) study offered trio RGS for diagnosis of critically ill children with a likely monogenic disorder. Main and actionable secondary findings were reported. Semi-structured interviews were conducted with parents of children offered RGS (n = 11) and professionals (genetic clinicians, non-genetic clinicians, scientists and consenters) (n = 19) by telephone (parents n = 10/professionals n = 1) or face-to-face (parents n = 1/professionals n = 18). We found that participants held largely positive views about RGS, describing clinical and emotional benefits from the opportunity to obtain a rapid diagnosis. Parental stress surrounding their child's illness complicates decision making. Parental concerns are heightened when offered RGS and while waiting for results. The importance of multidisciplinary team working to enable efficient delivery of a rapid service was emphasised. Our findings give insight into the perceived value of RGS for critically ill children. Careful pre-test counselling is needed to support informed parental decision making. Many parents would benefit from additional support while waiting for results. Education of mainstream clinicians is required to facilitate clinical implementation.

The 100,000 Genomes Project is a hybrid clinical and research project in which patients and parents are offered genome sequencing for cancer and rare and inherited disease diagnosis; all participants receive their main findings and contribute their data for research, and are offered optional secondary findings. Our aim was to explore participating parents' attitudes towards and understanding of genome sequencing in this hybrid context. We conducted in-depth telephone interviews with 20 parents of children with rare diseases participating in the 100,000 Genomes Project. Parents were positive about contributing to research, although some had needed reassurance about data protections. Although most felt positive about secondary findings, some could not recall or misunderstood key aspects. Some were also concerned about potential emotional impact of results and a few raised concerns about life insurance implications, and the impact of future legal changes. Participants were generally positive about consent appointments, but several raised concerns about 'information overload' because of deciding about secondary findings at the same time as about the main diagnostic genome sequencing and data contribution. Additional information resources, particularly online tools, were highlighted as potentially useful ways of supporting the consent process. We conclude that parents offered genome sequencing as part of a national hybrid clinical and research project report many positive attitudes and experiences, but also concerns and misunderstandings. Further research is needed on how best to support informed consent, particularly about secondary findings. Additional resources such as online tools might usefully support future genome sequencing consent processes.

Introduction: The advent of affordable and rapid next-generation sequencing has been transformative for prenatal diagnosis. Sequencing of cell-free DNA in maternal plasma has enabled the development of not only a highly sensitive screening test for fetal aneuploidies, but now definitive noninvasive prenatal diagnosis for monogenic disorders at an early gestation. Sequencing of fetal exomes offers broad diagnostic capability for pregnancies with unexpected fetal anomalies, improving the yield and accuracy of diagnoses and allowing better counseling for parents. The challenge now is to translate these approaches into mainstream use in the clinic. Areas covered: Here, the authors review the current literature to describe the technologies available and how these have evolved. The opportunities and challenges at hand, including considerations for service delivery, counseling, and development of ethical guidelines, are discussed. Expert commentary: As technology continues to advance, future developments may be toward noninvasive fetal whole exome or whole genome sequencing and a universal method for noninvasive prenatal diagnosis without the need to sequence both parents or an affected proband. Expansion of cell-free fetal DNA analysis to include the transcriptome and the methylome is likely to yield clinical benefits for monitoring other pregnancy-related pathologies such as preeclampsia and intrauterine growth restriction.

Emerging genomic technologies, largely based around next generation sequencing (NGS), are offering new promise for safer prenatal genetic diagnosis. These innovative approaches will improve screening for fetal aneuploidy, allow definitive non-invasive prenatal diagnosis (NIPD) of single gene disorders at an early gestational stage without the need for invasive testing, and improve our ability to detect monogenic disorders as the aetiology of fetal abnormalities. This presents clinicians and scientists with novel challenges as well as opportunities. In addition, the transformation of prenatal genetic testing arising from the introduction of whole genome, exome and targeted NGS produces unprecedented volumes of data requiring complex analysis and interpretation. Now translating these technologies to the clinic has become the goal of clinical genomics, transforming modern healthcare and personalized medicine. The achievement of this goal requires the most progressive technological tools for rapid high-throughput data generation at an affordable cost. Furthermore, as larger proportions of patients with genetic disease are identified we must be ready to offer appropriate genetic counselling to families and potential parents. In addition, the identification of novel treatment targets will continue to be explored, which is likely to introduce ethical considerations, particularly if genome editing techniques are included in these targeted treatments and transferred into mainstream personalized healthcare. Here we review the impact of NGS technology to analyse cell-free DNA (cfDNA) in maternal plasma to deliver NIPD for monogenic disorders and allow more comprehensive investigation of the abnormal fetus through the use of exome sequencing., (Copyright © 2017. Published by Elsevier Ltd.)

Objective:  To investigate the benefits and costs of implementing non-invasive prenatal testing (NIPT) for Down's syndrome into the NHS maternity care pathway., Design:  Prospective cohort study., Setting:  Eight maternity units across the United Kingdom between 1 November 2013 and 28 February 2015., Participants:  All pregnant women with a current Down's syndrome risk on screening of at least 1/1000., Main Outcome Measures:  Outcomes were uptake of NIPT, number of cases of Down's syndrome detected, invasive tests performed, and miscarriages avoided. Pregnancy outcomes and costs associated with implementation of NIPT, compared with current screening, were determined using study data on NIPT uptake and invasive testing in combination with national datasets., Results:  NIPT was prospectively offered to 3175 pregnant women. In 934 women with a Down's syndrome risk greater than 1/150, 695 (74.4%) chose NIPT, 166 (17.8%) chose invasive testing, and 73 (7.8%) declined further testing. Of 2241 women with risks between 1/151 and 1/1000, 1799 (80.3%) chose NIPT. Of 71 pregnancies with a confirmed diagnosis of Down's syndrome, 13/42 (31%) with the diagnosis after NIPT and 2/29 (7%) after direct invasive testing continued, resulting in 12 live births. In an annual screening population of 698 500, offering NIPT as a contingent test to women with a Down's syndrome screening risk of at least 1/150 would increase detection by 195 (95% uncertainty interval -34 to 480) cases with 3368 (2279 to 4027) fewer invasive tests and 17 (7 to 30) fewer procedure related miscarriages, for a non-significant difference in total costs (£-46 000, £-1 802 000 to £2 661 000). The marginal cost of NIPT testing strategies versus current screening is very sensitive to NIPT costs; at a screening threshold of 1/150, NIPT would be cheaper than current screening if it cost less than £256. Lowering the risk threshold increases the number of Down's syndrome cases detected and overall costs, while maintaining the reduction in invasive tests and procedure related miscarriages., Conclusions:  Implementation of NIPT as a contingent test within a public sector Down's syndrome screening programme can improve quality of care, choices for women, and overall performance within the current budget. As some women use NIPT for information only, the Down's syndrome live birth rate may not change significantly. Future research should consider NIPT uptake and informed decision making outside of a research setting., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Purpose of Review: To explore stakeholder views on cell-free DNA testing and highlight findings important for successful implementation and the provision of best practice in counseling., Recent Findings: Noninvasive tests based on the analysis of cell-free fetal DNA are now widely available in clinical practice and applications are expanding rapidly. It is essential that stakeholder views are considered in order to identify and address any ethical and social issues. We provide an overview of stakeholder viewpoints and then focus on the key issues of informed decision making, test uptake, service delivery and information sources., Summary: Stakeholders are positive about the introduction of cell-free fetal DNA testing into clinical practice. They describe both practical and psychological benefits arising from tests that are safe and can potentially be performed earlier in pregnancy. Key concerns, which include the potential for these tests to have a negative impact on informed decision making and increased societal pressure to have testing, can be addressed through careful parent-directed counseling. As applications for these tests expand it is increasingly important to develop innovative approaches to facilitate good understanding for parents who are offered noninvasive prenatal testing.

The use of massively parallel sequencing of maternal cfDNA for non-invasive prenatal testing (NIPT) of aneuploidy is widely available. Recently, the scope of testing has increased to include selected subchromosomal abnormalities, but the number of samples reported has been small. We developed a calling pipeline based on a segmentation algorithm for the detection of these rearrangements in maternal plasma. The same read depth used in our standard pipeline for aneuploidy NIPT detected 15/18 (83%) samples with pathogenic rearrangements > 6 Mb but only 2/10 samples with rearrangements < 6 Mb, unless they were maternally inherited. There were two false-positive calls in 534 samples with no known subchromosomal abnormalities (specificity 99.6%). Using higher read depths, we detected 29/31 fetal subchromosomal abnormalities, including the three samples with maternally inherited microduplications. We conclude that test sensitivity is a function of the fetal fraction, read depth, and size of the fetal CNV and that at least one of the two false negatives is due to a low fetal fraction. The lack of an independent method for determining fetal fraction, especially for female fetuses, leads to uncertainty in test sensitivity, which currently has implications for this technique's future as a clinical diagnostic test. Furthermore, to be effective, NIPT must be able to detect chromosomal rearrangements across the whole genome for a very low false-positive rate. Because standard NIPT can only detect the majority of larger (>6 Mb) chromosomal rearrangements and requires knowledge of fetal fraction, we consider that it is not yet ready for routine clinical implementation., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Prenatal testing based on cell-free fetal DNA in maternal serum is now possible for specific monogenic conditions, and studies have shown that the use of non-invasive testing is supported by prospective parents and health professionals. However, some ethical issues have been raised concerning informed consent and paternal rights. The objective of this study was to explore ethical aspects of the use of non-invasive prenatal diagnostic testing for autosomal recessive disorders. We used a qualitative cross-sectional design, based on Thematic Analysis, and recruited 27 individuals of reproductive age who were carriers of one of four conditions: thalassaemia, sickle cell disease, cystic fibrosis or spinal muscular atrophy. Data were collected via focus groups or interviews. Participants were aware of the potential for such tests to be viewed as routine and suggested that obtaining written consent and allowing time for consideration is needed to facilitate autonomous choice and informed consent. All participants felt that mothers should be able to request such tests, but fathers who declined carrier testing should be made aware that fetal test results may reveal their status. We suggest that a written record of consent for non-invasive prenatal diagnosis should be used as a standard to help reinforce the serious nature of the test results. Where the father's carrier status could be revealed through fetal testing, he should be made aware of this before the results are available. Health professionals should discuss with the pregnant woman the best way to manage unsought information about the father's carrier status to minimise family disruption.

Objective: Accurate prenatal diagnosis of genetic conditions can be challenging and usually requires invasive testing. Here, we demonstrate the potential of next-generation sequencing (NGS) for the analysis of cell-free DNA in maternal blood to transform prenatal diagnosis of monogenic disorders., Methods: Analysis of cell-free DNA using a PCR and restriction enzyme digest (PCR-RED) was compared with a novel NGS assay in pregnancies at risk of achondroplasia and thanatophoric dysplasia., Results: PCR-RED was performed in 72 cases and was correct in 88.6%, inconclusive in 7% with one false negative. NGS was performed in 47 cases and was accurate in 96.2% with no inconclusives. Both approaches were used in 27 cases, with NGS giving the correct result in the two cases inconclusive with PCR-RED., Conclusion: NGS provides an accurate, flexible approach to non-invasive prenatal diagnosis of de novo and paternally inherited mutations. It is more sensitive than PCR-RED and is ideal when screening a gene with multiple potential pathogenic mutations. These findings highlight the value of NGS in the development of non-invasive prenatal diagnosis for other monogenic disorders., (© 2015 John Wiley & Sons, Ltd.)

Objective: To investigate how non-invasive prenatal testing (NIPT) is portrayed in the UK press media., Methods: Content analysis of the ten most widely circulated print/digital news sources in the UK., Results: Seventy-nine articles were identified focusing on NIPT for Down syndrome (n = 67) including single gene disorders (n = 5), whole genome sequencing (n = 8), NIPT technology (n = 2), Rhesus D (n = 1) and fetal sex determination (n = 1). The majority (63%) were in 'serious' papers. Test attributes were frequently cited (100%), in particular that NIPT is a blood test (89%) and avoids risk of miscarriage (56%). The main psychosocial benefit reported was increased time for decision-making (15%). Concerns were discussed less frequently than benefits (39%), with increase in termination rates the main concern raised (23%). The majority of headlines (52%) projected a positive frame towards NIPT. Regarding overall framing of articles, over two thirds (68%) presented benefits and concerns or limitations; however, only a third (35%) were considered 'balanced'., Conclusion: Positive reporting of NIPT in the UK news media reflects the publics' broadly optimistic view towards genomic technology and prenatal testing. Health professionals should be aware that women may have incomplete information or misunderstandings about NIPT. Pre-test counselling to ensure informed decision-making is therefore important., (© 2014 John Wiley & Sons, Ltd.)

Background: Non-invasive prenatal testing (NIPT) for aneuploidies is now available through commercial companies in many countries, including through private practice in the United Kingdom (UK). Thorough evaluation of service delivery requirements are needed to facilitate NIPT being offered more widely within state funded healthcare systems such as the UK's National Health Service (NHS). Successful implementation will require the development of laboratory standards, consideration of stakeholder views, an analysis of costs and development of patient and health professional educational materials., Methods/design: NIPT will be offered in an NHS setting as a contingent screening test. Pregnant woman will be recruited through six maternity units in England and Scotland. Women eligible for Down's syndrome screening (DSS) will be informed about the study at the time of booking. Women that choose routine DSS will be offered NIPT if they have a screening risk ≥ 1:1000. NIPT results for trisomy 21, 18, 13 will be reported within 7-10 working days. Data on DSS, NIPT and invasive testing uptake, pregnancy outcomes and test efficacy will be collected. Additional data will be gathered though questionnaires to a) determine acceptability to patients and health professionals, b) evaluate patient and health professional education, c) assess informed choice in women accepting or declining testing and d) gauge family expenses. Qualitative interviews will also be conducted with a sub-set of participating women and health professionals., Discussion: The results of this study will make a significant contribution to policy decisions around the implementation of NIPT for aneuploidies within the UK NHS. The laboratory standards for testing and reporting, education materials and counselling strategies developed as part of the study are likely to underpin the introduction of NIPT into NHS practice., Nihr Portfolio Number: 13865.

Non-invasive prenatal testing for single gene disorders is now clearly on the horizon. This new technology offers obvious clinical benefits such as safe testing early in pregnancy. Before widespread implementation, it is important to consider the possible ethical implications. Four hypothetical scenarios are presented that highlight how ethical ideals of respect for autonomy, privacy and fairness may come into play when offering non-invasive prenatal testing for single gene disorders. The first scenario illustrates the moral case for using these tests for 'information only', identifying a potential conflict between larger numbers of women seeking the benefits of the test and the wider social impact of funding tests that do not offer immediate clinical benefit. The second scenario shows how the simplicity and safety of non-invasive prenatal testing could lead to more autonomous decision-making and, conversely, how this could also lead to increased pressure on women to take up testing. In the third scenario we show how, unless strong safeguards are put in place, offering non-invasive prenatal testing could be subject to routinisation with informed consent undermined and that woman who are newly diagnosed as carriers may be particularly vulnerable. The final scenario introduces the possibility of a conflict of the moral rights of a woman and her partner through testing for single gene disorders. This analysis informs our understanding of the potential impacts of non-invasive prenatal testing for single gene disorders on clinical practice and has implications for future policy and guidelines for prenatal care.

Recently, we have witnessed the rapid translation into clinical practice of non-invasive prenatal testing for the common aneuploidies, most notably within the United States and China. This represents a lucrative market with testing being driven by companies developing and offering their services. These tests are currently aimed at women with high/medium-risk pregnancies identified by serum screening and/or ultrasound scanning. Uptake has been impressive, albeit limited to the commercial sector. However, non-invasive prenatal diagnosis (NIPD) for single-gene disorders has attracted less interest, no doubt because this represents a much smaller market opportunity and in the majority of cases has to be provided on a bespoke, patient or disease-specific basis. The methods and workflows are labour-intensive and not readily scalable. Nonetheless, there exists a significant need for NIPD of single-gene disorders, and the continuing advances in technology and data analysis should facilitate the expansion of the NIPD test repertoire. Here, we review the progress that has been made to date, the different methods and platform technologies, the technical challenges, and assess how new developments may be applied to extend testing to a wider range of genetic disorders., (© 2013 John Wiley & Sons, Ltd.)

Disorders of sex development (DSD) rarely present prenatally but, as they are very complex conditions, management should be directed by highly specialised medical teams to allow consideration of all aspects of diagnosis, treatment and ethical issues. In this brief review, we present an overview of the prenatal presentation and management of DSD, including the sonographic appearance of normal genitalia and methods of determining genetic sex, the prenatal management of pregnancies with the unexpected finding of genital ambiguity on prenatal ultrasound and a review of the prenatal management of pregnancies at high risk of DSD. As this is a rapidly developing field, management options will change over time, making the involvement of clinical geneticists, paediatric endocrinologists and urologists, as well as fetal medicine specialists, essential in the care of these complex pregnancies. The reader should also bear in mind that local social, ethical and legal aspects may also influence management., (Copyright © 2012 Journal of Pediatric Urology Company. All rights reserved.)

Background: Non-invasive prenatal testing (NIPT) for Down’s syndrome (DS) using cell free fetal DNA in maternal blood has the potential to dramatically alter the way prenatal screening and diagnosis is delivered. Before NIPT can be implemented into routine practice, information is required on its costs and benefits. We investigated the costs and outcomes of NIPT for DS as contingent testing and as first-line testing compared with the current DS screening programme in the UK National Health Service. Methods: We used a pre-existing model to evaluate the costs and outcomes associated with NIPT compared with the current DS screening programme. The analysis was based on a hypothetical screening population of 10,000 pregnant women. Model inputs were taken from published sources. The main outcome measures were number of DS cases detected, number of procedure-related miscarriages and total cost. Results: At a screening risk cut-off of 1∶150 NIPT as contingent testing detects slightly fewer DS cases, has fewer procedure-related miscarriages, and costs the same as current DS screening (around UK£280,000) at a cost of £500 per NIPT. As first-line testing NIPT detects more DS cases, has fewer procedure-related miscarriages, and is more expensive than current screening at a cost of £50 per NIPT. When NIPT uptake increases, NIPT detects more DS cases with a small increase in procedure-related miscarriages and costs. Conclusions: NIPT is currently available in the private sector in the UK at a price of £400-£900. If the NHS cost was at the lower end of this range then at a screening risk cut-off of 1∶150 NIPT as contingent testing would be cost neutral or cost saving compared with current DS screening. As first-line testing NIPT is likely to produce more favourable outcomes but at greater cost. Further research is needed to evaluate NIPT under real world conditions. [ABSTRACT FROM AUTHOR]