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Plain language summary: Structural differences (congenital anomalies) in the makeup of the baby's heart, brain and other organs are found on antenatal ultrasound scans in up to 3% of pregnancies. These often have a genetic cause, arising because of changes in the chromosomes (which store our genetic material) or the DNA code that make up the genes. The more differences a baby has the more likely the risk of underlying genetic disease. If a structural difference is found, parents are usually offered a genetic test, which may be carried out on cells taken either from the placenta (chorionic villous sampling) or the fluid surrounding the baby (amniocentesis). At the moment, these cells are only tested for changes in the chromosomes and are only able to reveal the underlying cause in about 40% of unborn babies. Prenatal exome sequencing (ES) is a new genetic test, which, when combined with testing the DNA of both parents can find changes in the baby's genetic code. If a DNA change is found that can explain the structural changes seen on ultrasound, specific information about the underlying diagnosis can be given to the parents. Having this information can help parents make important decisions about their ongoing pregnancy, as well as help doctors to care for the mother and baby. Finding a genetic change can also help to understand how the condition has arisen and whether it might happen again in another pregnancy. It may also be possible to test for the genetic condition in future pregnancies. Although prenatal ES is an exciting new way to improve diagnosis rates for structural differences, it has some challenges. While the test is very detailed, it may not always find a genetic explanation and sometimes the results are difficult to interpret. For example, genetic changes can be found where their significance for the pregnancy is unclear. More recently, two studies have now shown that prenatal ES can find a genetic diagnosis in at least 10% of pregnancies with structural differences where standard chromosome testing has been negative. This paper reviews these studies, along with earlier evidence on ES and provides clinicians with guidance for future practice. [ABSTRACT FROM AUTHOR]

Objective To assess the views and likely uptake of non-invasive prenatal testing ( NIPT) for trisomy 21 among potential service users in the UK. Design Cross-sectional survey. Setting Four antenatal clinics in England and two websites. Sample A total of 1131 women and partners. Methods Questionnaire conducted with women (and partners) recruited through antenatal clinics, a random sample of members of the website Mumsnet, and viewers of the website and Facebook page of the support group Antenatal Results and Choices ( ARC). Main outcome measures Factors impacting decision-making towards prenatal testing; views on NIPT, including service delivery and likely uptake; hypothetical scenarios, focused on current screening, invasive testing, and NIPT offered to women with a high-risk screening result. Results The vast majority (95.7%; 1071/1119; 95% CI 94.4-96.8%) thought NIPT was a positive development in prenatal care, with 88.2% (972/1103; 95% CI 86.1-90%) indicating that they would use the test, including respondents who would currently decline trisomy 21 screening ( P < 0.001). Of the respondents who would have NIPT, 30.7% (299/973; 95% CI = 27.8-33.7%) said that they were 'likely' to terminate an affected pregnancy (including those who would currently decline screening or invasive testing), and 36.5% (355/973; 95% CI 33.5-39.6%) were 'not likely' to terminate an affected pregnancy. Respondents overwhelmingly indicated that safety for the baby was the most important attribute of NIPT (70.1%; 712/1015; 95% CI 67.2-73%). Conclusion Respondents were overwhelmingly positive towards the introduction of NIPT. Uptake is likely to be high, and includes women who currently decline screening as well as those who will use the test for information only. Pre-test counselling to ensure that women understand the implications of the test result is essential. [ABSTRACT FROM AUTHOR]

Objective: Perinatal autopsy provides additional diagnostic information in a significant proportion of cases but parents and relatives frequently decline traditional postmortem (PM) examination, partly due to the unacceptability of the cosmetic effects of large incisions and concerns regarding organ retention. We present a novel minimally invasive autopsy method for fetal and neonatal PMexaminations, which includes PM magnetic resonance imaging (MRI) for assessment of anatomy and endoscopic internal examination to allow direct organ visualization and targeted tissue biopsy.Methods: Descriptive retrospective feasibility report of the first 10 perinatal cases undergoing endoscopic minimally invasive autopsy.Results: A minimally invasive autopsy (MIA) approach based on postmortem MRI (PM MRI) and endoscopic autopsy with tissue biopsy is feasible and effective with minimal cosmetic consequences compared to traditional PM examination. Endoscopic examination with tissue biopsy provided additional diagnostic information to PM MRI alone in the majority of cases.Conclusions: Endoscopic MIA is a feasible and potentially more acceptable approach to perinatal autopsy and provides an additional option for parents who do not agree to a traditional PM examination. This approach could result in increased utilization of investigations after death in this group of patients. [ABSTRACT FROM AUTHOR]

Folic acid supplementation can prevent many cases of neural tube defects (NTDs), whereas suboptimal maternal folate status is a risk factor, suggesting that folate metabolism is a key determinant of susceptibility to NTDs. Despite extensive genetic analysis of folate cycle enzymes, and quantification of metabolites in maternal blood, neither the protective mechanism nor the relationship between maternal folate status and susceptibility are understood in most cases. In order to investigate potential abnormalities in folate metabolism in the embryo itself, we derived primary fibroblastic cell lines from foetuses affected by NTDs and subjected them to the dU suppression test, a sensitive metabolic test of folate metabolism. Significantly, a subset of NTD cases exhibited low scores in this test, indicative of abnormalities in folate cycling that may be causally linked to the defect. Susceptibility to NTDs may be increased by suppression of the methylation cycle, which is interlinked with the folate cycle. However, reduced efficacy in the dU suppression test was not associated with altered abundance of the methylation cycle intermediates, s-adenosylmethionine and s-adenosylhomocysteine, suggesting that a methylation cycle defect is unlikely to be responsible for the observed abnormality of folate metabolism. Genotyping of samples for known polymorphisms in genes encoding folate-associated enzymes did not reveal any correlation between specific genotypes and the observed abnormalities in folate metabolism. These data suggest that as yet unrecognized genetic variants result in embryonic abnormalities of folate cycling that may be causally related to NTDs. [ABSTRACT FROM AUTHOR]

Introduction In October 2020, a national rapid prenatal exome sequencing (pES) service was rolled out across the English National Health Service (NHS). This service is delivered by multiple clinical and two laboratory teams. Whilst there was high level national guidance to support implementation, it was unclear how the service has been delivered in practice. This study evaluated pES service implementation across England, using the Major System Change Framework to explore links between implementation approaches and outcomes. Methods We conducted a national mixed-methods multi-site study of 17 clinical genomics services, their linked fetal medicine services and two laboratories delivering the pES service. The Major System Change Framework informed the study. Key documents, semi-structured interviews (eight national service developers, 55 staff), and surveys (n=159 staff) were analysed using inductive and deductive thematic analysis and descriptive statistics. Findings were integrated. Results Implementation was influenced by a range of factors including evidence of benefit, laboratory service reconfiguration and stakeholder support. Local implementation approaches varied; seven models of service delivery were identified. Key differences between models included leadership, staffing and multidisciplinary team (MDT) approaches. Local staff factors (e.g. time, capacity, attitudes), pES service factors (e.g. communication/collaboration, logistics) and organisational factors (e.g. infrastructure and previous experience) influenced implementation. Conclusion We have identified multiple barriers and facilitators that are associated with implementing a major change to genomic services in a complex national healthcare system. This study highlights which models of pES may work in practice and why. Findings will inform future development of the pES service., (The Author(s). Published by S. Karger AG, Basel.)

Objective: Accurate recurrence risks are essential for genomic counselling and parental reproductive choices. Historically, Sanger sequencing was used to test parental samples, which has a limited sensitivity of ∼ 10% for detecting somatic mosaicism. Next generation sequencing (NGS) methods, utilised for non-invasive prenatal diagnosis (NIPD) and trio prenatal exome sequencing in our laboratory, have greater sensitivity. Here we review the cases of parental somatic mosaicism we have detected and discuss its impact on management., Method: Laboratory databases from 1 January 2015 to 30 September 2022 were reviewed to identify all cases where parental somatic mosaicism was detected during NIPD and prenatal exome testing., Results: During the development of NIPD testing, we identified 10/131 (7.6%) families with parental somatic mosaicism. In six cases where NGS detected levels between 0.37% and 8.82%, prior testing with Sanger sequencing had not detected mosaicism. In our exome sequencing cohort, we detected parental mosaicism in 4/101 (3.96%) cases. Clinical features of the condition were identified in 2/14 parents., Conclusion: The sensitivity of the testing technique needs to be considered when counselling parents on recurrence risk. Parents need to be aware that modern approaches to prenatal diagnosis may allow identification of mosaicism, which may have implications for their own health and change recurrence risks for future pregnancies., (© 2024 The Author(s). Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objective: Prenatal exome sequencing (pES) for diagnosing fetal structural anomalies commenced in the English National Health Service (NHS) in 2020. We evaluated cost-effectiveness to the healthcare system, and costs to families, of pES in addition to standard testing, compared to standard testing alone., Design: A cost-effectiveness analysis combining costs, outcomes, parent and professional interview and professional survey data., Setting: The English NHS Genomic Medicine Service., Sample: 413 families with fetal anomalies with a suspected genetic cause referred for pES from 01 October 2021 to 30 June 2022., Methods: We costed the incremental resource required to deliver the pES clinical pathway. We calculated the diagnostic yield (proportion of cases with pathogenic variants). We divided the total incremental cost by the number of cases with a diagnosis to calculate cost-effectiveness. We estimated the annual NHS budget requirement based on case numbers. We determined parental costs from interviews., Main Outcome Measures: Incremental costs of pES to the NHS and families, incremental cost per additional diagnosis and NHS budget impact., Results: Of 413 referred cases, 241 were tested, at a cost of £2331 (95% credibility interval £1894-£2856) per referred case or £3592 (£2959-£4250) per case that proceeded with testing. The incremental cost per diagnosis (yield 35.3%) was £11 326 (£8582-£15 361). Based on referrals data 01 October 2022 to 30 September 2023, pES costs the NHS £1.8 m annually. Family costs could not be separated from other pregnancy-related appointments but were not considered burdensome; most appointments were concurrent or remote., Conclusion: pES costs the English NHS £11 326 for each additional diagnosis. Incremental costs to families are negligible., (© 2024 The Author(s). BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Introduction: Prenatal exome sequencing (pES) can enhance genetic diagnosis of fetuses with structural anomalies and has recently been introduced as a national service in England. We aimed to examine service outcomes such as diagnostic yield (definite final diagnosis), referral rate, and sources of referral, and explore variation in outcomes of pES by individual or service level factors between 01 October 2021 and 30 June 2022., Methods: pES testing results from the National Health Service laboratories performing testing were linked to National Congenital Anomaly and Rare Disease Registration Service data and the Maternity Services Data Set and descriptive statistics computed., Results: There were 475,089 women who gave birth in England during the study period. The referral rate for pES was 8.6 (95% CI 7.8, 9.4) per 10,000 maternities. About 59% of those referred proceeded with pES testing and 35% of women who proceeded received a definite final diagnosis with a median turnaround time of 15 days. Of those who had pES testing, 64.6% had a live birth, 25.3% underwent termination of pregnancy (median gestational age at termination: 26 weeks), and 9.3% had a stillbirth. Among the 85 women who had a definite final diagnosis, 40% had a termination of pregnancy, 18% had a stillbirth, and 42% had a live birth. The corresponding figures among women without a definite final diagnosis were 18%, 5%, and 78%, respectively. Among women who had a termination of pregnancy, the median gestational age at final report was 24.9 weeks and 26.2 weeks at termination. Variation observed in some of the characteristics and outcomes between regional services were limited by small sample size., Conclusion: This study showed that of those referred, pES testing provided a diagnosis for one in three pregnancies with a fetal anomaly across England during the study period when other tests had been non-informative. Women who opted for a termination of pregnancy underwent the procedure at relatively late gestations. Earlier referral for pES, streamlining pathways, and faster turnaround times may help results to be available at an earlier gestation to allow families more time to make decisions around continuing or terminating their pregnancy. The variation in service outcomes between regional services needs to be investigated further to understand the reasons for these differences., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ramakrishnan, Mallinson, Hardy, Broughan, Blyth, Melis, Franklin, Hill, Mellis, Wu, Allen, Chitty, Knight and EXPRESS Clinical Outcomes Group.)

Participants in the 100,000 Genomes Project (100kGP) could consent to receive additional finding (AF) results, individual variants relating to genes associated with susceptibility to cancer and familial hypercholesterolemia (FH). In the study reported here, qualitative interviews were used to explore the experiences of National Health Service (NHS) professionals from across England who were tasked with returning over 80,000 "no AF" results and 700 positive AF results to 100kGP participants. Interviews were conducted with 45 professionals from a range of backgrounds, including Genetic Counsellors, Clinical Geneticists, FH Clinical Nurse Specialists and Clinical Scientists. Interviews were analysed using a codebook thematic analysis approach. Returning AF results has been a significant endeavour, with challenges for pathways, administrative processes and clinical and laboratory time when the capacity of NHS services is already stretched. Professionals discussed going "above and beyond" to prioritise patient care through pathway design, additional clinics, overtime, longer appointments and provision of follow-up appointments. Professionals also described facing practical and emotional challenges when returning AFs. Benefits for patients from receiving AFs in the 100kGP were highlighted and professionals were generally positive about offering clinically actionable AFs within routine NHS clinical care. Professionals were, however, cautious around the implementation of AFs into routine care and felt more research and discussion was needed to determine which AFs to offer, approaches to consent and communication of results, costs and the potential strain on NHS capacity and resources. Further consultation is required with careful review of pathways and resources before offering AFs in clinical practice., (© 2024. The Author(s).)

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., (© 2024. The Author(s).)

Background: Evidence suggests that coordination of care for people affected by rare diseases is poor. In order to improve the way that care is coordinated it is necessary to understand the preferences of people affected by these conditions, and providers. The aim of this study was to examine patient, parent and carer, and health care professional preferences for different attributes of care coordination for people affected by rare diseases. We conducted a discrete choice experiment using online surveys. There were no restrictions on participants in terms of rare conditions, demographic factors other than age, or geographical location within the UK. Choice scenarios were based on the following attributes: annual cost of attending appointments; access to health records; access to clinical expertise; support of a care coordinator; access to a specialist centre; and, the existence of a documented plan for emergency care. Data were analysed using alternative-specific conditional logit regression models., Results: Valid responses were obtained from 996 individuals (528 patients, 280 carers, 188 health care professionals) between August and December 2019. All attributes significantly influenced the type of service respondents preferred. Patients, carers and health professionals' preferences for care coordination were influenced by: the cost of attending appointments; access to health records; clinical expertise; role of care coordinators; access to specialist centres; and the existence of plan for emergency care. There were no statistically significant differences in the preferences between patients and carers. Preferences of health professionals differed to those of patients and carers. Both patients and carers selected responses which granted them a greater degree of autonomy in relation to the role of care coordinators, whereas health professionals preferred services where care coordinators had more autonomy. Health care professionals also expressed a stronger preference for a documented formal emergency plan to be in place., Conclusions: The findings highlight that people value better coordinated care, in line with policy documents emphasising commitments to coordinated care for people affected by rare diseases. This study highlights the factors that could be included in service provision as ways of improving the coordination of care for people affected by rare diseases., (© 2024. The Author(s).)

Clinical whole-genome sequencing (WGS) has been shown to deliver potential benefits to children with cancer and to alter treatment in high-risk patient groups. It remains unknown whether offering WGS to every child with suspected cancer can change patient management. We collected WGS variant calls and clinical and diagnostic information from 281 children (282 tumors) across two English units (n = 152 from a hematology center, n = 130 from a solid tumor center) where WGS had become a routine test. Our key finding was that variants uniquely attributable to WGS changed the management in ~7% (20 out of 282) of cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, in 108 instances for 83 (29%) cases. Furthermore, WGS faithfully reproduced every standard-of-care molecular test (n = 738) and revealed several previously unknown genomic features of childhood tumors. We show that WGS can be delivered as part of routine clinical care to children with suspected cancer and can change clinical management by delivering unexpected genomic insights. Our experience portrays WGS as a clinically impactful assay for routine practice, providing opportunities for assay consolidation and for delivery of molecularly informed patient care., (© 2024. The Author(s).)

Introduction: In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England, requiring the coordination of care from specialist genetics, fetal medicine (FM) and laboratory services. This mixed methods study explored the experiences of professionals involved in delivering the pES service during the first 2 years of its delivery in the NHS., Methods: A survey ( n = 159) and semi-structured interviews ( n = 63) with healthcare professionals, including clinical geneticists, FM specialists, and clinical scientists (interviews only) were used to address: 1) Views on the pES service; 2) Capacity and resources involved in offering pES; 3) Awareness, knowledge, and educational needs; and 4) Ambitions and goals for the future., Results: Overall, professionals were positive about the pES service with 77% rating it as Good or Excellent. A number of benefits were reported, including the increased opportunity for receiving actionable results for parental decision-making, improving equity of access to genomic tests and fostering close relationships between FM and genetics departments. Nonetheless, there was evidence that the shift to offering pES in a clinical setting had brought some challenges, such as additional clinic time, administrative processes, perceived lack of autonomy in decision-making regarding pES eligibility and difficulty engaging with peripheral maternity units. Concerns were also raised about the lack of confidence and gaps in genomics knowledge amongst non-genetics professionals - especially midwives. However, the findings also highlighted value in both FM, obstetric and genetics professionals benefiting from further training with a focus on recognising and managing prenatally diagnosed genetic conditions., Conclusion: Healthcare professionals are enthusiastic about the benefits of pES, and through multi-collaborative working, have developed relationships that have contributed to effective communication across specialisms. Although limitations on resources and variation in knowledge about pES have impacted service delivery, professionals were hopeful that improvements to infrastructure and the upskilling of all professionals involved in the pathway would optimise the benefits of pES for both parents and professionals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Peter, Mellis, McInnes-Dean, Daniel, Walton, Fisher, Leeson-Beevers, Allen, Baple, Beleza-Meireles, Bertoli, Campbell, Canham, Cilliers, Cobben, Eason, Harrison, Holder-Espinasse, Male, Mansour, McEwan, Park, Smith, Stewart, Tapon, Vasudevan, Williams, Wu, Chitty and Hill.)

Introduction: Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4., Methods and Analysis: BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in COL1A1 or COL1A2 can be included in the trial.Each subject receives four intravenous doses of 3×10 6 /kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover., Ethics and Dissemination: The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals., Trial Registration Numbers: EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482., Competing Interests: Competing interests: ALD is a consultant for Esperare Foundation for a clinical trial unrelated to this work. CG, LW-J and MW are cofounders and coowners of BOOST Pharma ApS founded in 2020. OS is a scientific advisor for BOOST Pharma ApS., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To determine the incremental yield of prenatal exome sequencing (PES) over standard testing in fetuses with an isolated congenital heart abnormality (CHA), CHA associated with extra-cardiac malformations (ECMs) and CHA dependent upon anatomical subclassification., Methods: A systematic review of the literature was performed using MEDLINE, EMBASE, Web of Science and grey literature January 2010-February 2023. Studies were selected if they included greater than 20 cases of prenatally diagnosed CHA when standard testing (QF-PCR/chromosome microarray/karyotype) was negative. Pooled incremental yield was determined. PROSPERO CRD 42022364747., Results: Overall, 21 studies, incorporating 1957 cases were included. The incremental yield of PES (causative pathogenic and likely pathogenic variants) over standard testing was 17.4% (95% CI, 13.5%-21.6%), 9.3% (95% CI, 6.6%-12.3%) and 35.9% (95% CI, 21.0%-52.3%) for all CHAs, isolated CHAs and CHAs associated with ECMs. The subgroup with the greatest yield was complex lesions/heterotaxy; 35.2% (95% CI 9.7%-65.3%). The most common syndrome was Kabuki syndrome (31/256, 12.1%) and most pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease causing genes (114/224, 50.9%)., Conclusion: The likelihood of a monogenic aetiology in fetuses with multi-system CHAs is high. Clinicians must consider the clinical utility of offering PES in selected isolated cardiac lesions., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Background: Cell-free fetal DNA exists within the maternal bloodstream during pregnancy and provides a means for noninvasive prenatal diagnosis (NIPD). Our accredited clinical service offers definitive NIPD for several autosomal recessive (AR) and X-linked conditions using relative haplotype dosage analysis (RHDO). RHDO involves next-generation sequencing (NGS) of thousands of common single nucleotide polymorphism (SNPs) surrounding the gene of interest in the parents and an affected or unaffected offspring to conduct haplotype phasing of the high- and low-risk alleles. NGS is carried out in parallel on the maternal cell-free DNA, and fetal inheritance is predicted using sensitive dosage calculations performed at sites where the parental genotypes differ. RHDO is not currently offered to consanguineous couples owing to the shared haplotype between parents. Here we test the expansion of RHDO for AR monogenic conditions to include consanguineous couples., Methods: The existing sequential probability ratio test analysis pipeline was modified to apply to SNPs where both parents are heterozygous for the same genotype. Quality control thresholds were developed using 33 nonconsanguineous cases. The performance of the adapted RHDO pipeline was tested on 8 consanguineous cases., Results: The correct fetal genotype was predicted by our revised RHDO approach in all conclusive cases with known genotypes (n = 5). Haplotype block classification accuracies of 94.5% and 93.9% were obtained for the nonconsanguineous and consanguineous case cohorts, respectively., Conclusions: Our modified RHDO pipeline correctly predicts the genotype in fetuses from consanguineous families, allowing the potential to expand access to NIPD services for these families., (© Association for Diagnostics & Laboratory Medicine 2024.)

Objectives: Determine the incremental diagnostic yield of prenatal exome sequencing (pES) over chromosome microarray (CMA) or G-banding karyotype in fetuses with central nervous system (CNS) abnormalities., Methods: Data were collected via electronic searches from January 2010 to April 2022 in MEDLINE, Cochrane, Web of Science and EMBASE. The NHS England prenatal exome cohort was also included. Incremental yield was calculated as a pooled value using a random-effects model., Results: Thirty studies were included (n = 1583 cases). The incremental yield with pES for any CNS anomaly was 32% [95%CI 27%-36%; I 2  = 72%]. Subgroup analysis revealed apparent incremental yields in; (a) isolated CNS anomalies; 27% [95%CI 19%-34%; I 2  = 74%]; (b) single CNS anomaly; 16% [95% CI 10%-23%; I 2  = 41%]; (c) more than one CNS anomaly; 31% [95% Cl 21%-40%; I 2  = 56%]; and (d) the anatomical subtype with the most optimal yield was Type 1 malformation of cortical development, related to abnormal cell proliferation or apoptosis, incorporating microcephalies, megalencephalies and dysplasia; 40% (22%-57%; I 2  = 68%). The commonest syndromes in isolated cases were Lissencephaly 3 and X-linked hydrocephalus., Conclusions: Prenatal exome sequencing provides a high incremental diagnostic yield in fetuses with CNS abnormalities with optimal yields in cases with multiple CNS anomalies, particularly those affecting the midline, posterior fossa and cortex., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objectives: In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England. This study aimed to explore parent experiences and their information and support needs from the perspective of parents offered pES and of health professionals involved in its delivery., Methods: In this qualitative study, semi-structured interviews were conducted with 42 women and 6 male partners and 63 fetal medicine and genetic health professionals. Interviews were transcribed verbatim and analysed using thematic analysis., Results: Overall views about pES were positive and parents were grateful to be offered the test. Highlighted benefits of pES included the value of the additional information for pregnancy management and planning for future pregnancies. An anxious wait for results was common, often associated with the need to make decisions near to 24 weeks in pregnancy when there are legal restrictions for late termination. Descriptions of dealing with uncertainty were also common, even when results had been returned. Many parents described pES results as informing decision-making around whether or not to terminate pregnancy. Some professionals were concerned that a non-informative result could be overly reassuring and highlighted that careful counselling was needed to ensure parents have a good understanding of what the result means for their pregnancy. Emotional support from professionals was valued; however, some parents felt that post-test support was lacking., Conclusion: Parents and professionals welcomed the introduction of pES. Results inform parents' decision-making around the termination of pregnancy. When there are no diagnostic findings or uncertain findings from pES, personalised counselling that considers scans and other tests are crucial. Directing parents to reliable online sources of information and providing emotional support throughout could improve their experiences of care., (© 2024 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Noninvasive cfDNA testing for monogenic disorders (sgNIPT) has become integrated into the care of pregnant women at increased risk based on carrier status, known family history, or ultrasound anomalies. The availability of commercial tests for common autosomal recessive and de novo autosomal dominant conditions has led to the use of these tests in low-risk pregnancies. However, is the technology ready for use in this low-risk population? This report is a summary of the debate on this topic at the 27 th International Conference on Prenatal Diagnosis and Therapy. Both expert debaters provided strong arguments in favor and against the use of sgNIPT in low-risk pregnancies. The argument in favor of sgNIPT for autosomal recessive conditions is that it allows the identification of affected pregnancies without the need for involving the partner in testing. Arguments for sgNIPT for autosomal dominant conditions include identification of affected fetuses that would have either presented later in pregnancy with fetal anomalies or not been detected prenatally given normal ultrasounds, respect for patient autonomy and patient desire for information. Strong arguments were made against offering sgNIPT screening. Given that traditional carrier screening for recessive conditions can be carried out in many jurisdictions, the added value of sgNIPT has not been clearly demonstrated. Arguments against sgNIPT for autosomal dominant conditions included the total lack of clinical validation studies and the risk of false reassurance in cases of negative results and unnecessary invasive procedures in cases of false positive results. Although there is a desire to take advantage of new technologies to improve the detection of monogenic disorders in low-risk populations, based on the discussion and the audience vote, it appears premature to offer sgNIPT to all low risk pregnant women. Further clinical validation studies are needed prior to broad implementation., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)