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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. [ABSTRACT FROM AUTHOR]

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 27th 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. Key points: What's already known about this topic?cfDNA testing on maternal blood is technically possible and commercially available for dominant and recessive monogenic conditions. What does the study add?This report summarizes an oral debate presented at the 27th International Conference on Prenatal Diagnosis and Therapy in Edinburgh, UK on June 20th, 2023.The benefits, limitations and challenges of performing cfDNA screening for monogenic conditions in low‐risk populations are discussed. [ABSTRACT FROM AUTHOR]

Background: Poorly coordinated care can have major impacts on patients and families affected by rare conditions, with negative physical health, psychosocial and financial consequences. This study aimed to understand how care is coordinated for rare diseases in the United Kingdom. Methods: We undertook a national survey in the UK involving 760 adults affected by rare diseases, 446 parents/carers of people affected by rare diseases, and 251 healthcare professionals who care for people affected by rare diseases. Results: Findings suggested that a wide range of patients, parents and carers do not have coordinated care. For example, few participants reported having a care coordinator (12% patients, 14% parents/carers), attending a specialist centre (32% patients, 33% parents/carers) or having a care plan (10% patients, 44% parents/carers). A very small number of patients (2%) and parents/carers (5%) had access to all three—a care coordinator, specialist centre and care plan. Fifty four percent of patients and 33% of parents/carers reported access to none of these. On the other hand, a higher proportion of healthcare professionals reported that families with rare conditions had access to care coordinators (35%), specialist centres (60%) and care plans (40%). Conclusions: Care for families with rare conditions is generally not well coordinated in the UK, with findings indicating limited access to care coordinators, specialist centres and care plans. Better understanding of these issues can inform how care coordination might be improved and embrace the needs and preferences of patients and families affected by rare conditions. [ABSTRACT FROM AUTHOR]

Primary mitochondrial diseases (PMDs) comprise a large and heterogeneous group of genetic diseases that result from pathogenic variants in either nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Widespread adoption of next-generation sequencing (NGS) has improved the efficiency and accuracy of mtDNA diagnoses; however, several challenges remain. In this review, we briefly summarize the current state of the art in molecular diagnostics for mtDNA and consider the implications of improved whole genome sequencing (WGS), bioinformatic techniques, and the adoption of long-read sequencing, for PMD diagnostics. We anticipate that the application of PCR-free WGS from blood DNA will increase in diagnostic laboratories, while for adults with myopathic presentations, WGS from muscle DNA may become more widespread. Improved bioinformatic strategies will enhance WGS data interrogation, with more accurate delineation of mtDNA and NUMTs (nuclear mitochondrial DNA segments) in WGS data, superior coverage uniformity, indirect measurement of mtDNA copy number, and more accurate interpretation of heteroplasmic large-scale rearrangements (LSRs). Separately, the adoption of diagnostic long-read sequencing could offer greater resolution of complex LSRs and the opportunity to phase heteroplasmic variants. Mitochondria generate our bodies' energy, and they contain their own circular DNA molecules. Changes in this mitochondrial DNA can cause a wide range of genetic diseases. Improved computer processing of the sequence of this DNA and new techniques that can read the full DNA sequence in one experiment may enhance our ability to understand these genetic variants. [ABSTRACT FROM AUTHOR]

Key points: What is already known about this topic? In 2015, the International Society for Prenatal Diagnosis (ISPD) published its first position statement on the use of non‐invasive prenatal testing (NIPT) to screen for aneuploidy. Widespread uptake across the globe and subsequent published research has shed new light on test performance and implementation issues. What does this study add? This new position statement replaces the 2015 statement with updated information on the current technologies, clinical experience, and implementation practices.As an international organization, ISPD recognizes that there are important population‐specific considerations in the organization of prenatal screening and diagnosis. These opinions are designed to apply to high income settings where prenatal screening for aneuploidy is an established part of antenatal care.This position statement is not a clinical practice guideline but represents the consensus opinion of the current ISPD Board based on the current state of knowledge and clinical practice. [ABSTRACT FROM AUTHOR]

Objectives: To develop a flexible droplet digital PCR (ddPCR) workflow to perform non‐invasive prenatal diagnosis via relative mutation dosage (RMD) for maternal pathogenic variants with a range of inheritance patterns, and to compare the accuracy of multiple analytical approaches. Methods: Cell free DNA (cfDNA) was tested from 124 archived maternal plasma samples: 88 cases for sickle cell disease and 36 for rare Mendelian conditions. Three analytical methods were compared: sequential probability ratio testing (SPRT), Bayesian and z‐score analyses. Results: The SPRT, Bayesian and z‐score analyses performed similarly well with correct prediction rates of 96%, 97% and 98%, respectively. However, there were high rates of inconclusive results for each cohort, particularly for z‐score analysis which was 31% overall. Two samples were incorrectly classified by all three analytical methods; a false negative result predicted for a fetus affected with sickle cell disease and a false positive result predicting the presence of an X‐linked IDS variant in an unaffected fetus. Conclusions: ddPCR can be applied to RMD for diverse conditions and inheritance patterns, but all methods carry a small risk of erroneous results. Further evaluation is required both to reduce the rate of inconclusive results and explore discordant results in more detail. Key points: What is already know about this topic? Digital PCR can be used to determine the fetal genotype of single gene disorders by dosage analysis of cfDNA in maternal plasma.Previous studies have shown the feasibility of this approach with small sample cohorts but reported rates of incorrect results are as high as 20%.Different statistical analysis methods have been reported, but their comparative accuracy has not been assessed. What does this study add? We report the results for digital PCR analysis on over 120 cfDNA samples and a large‐scale comparison of three different analytical approaches.Accounting for technical variation using z‐score analysis can significantly reduce incorrect fetal genotype predictions, but all three methods tested have a small residual error rate. [ABSTRACT FROM AUTHOR]

Cell-free fetal DNA (cffDNA) is released into the maternal circulation from trophoblastic cells during pregnancy, is detectable from 4 weeks and is representative of the entire fetal genome. The presence of this cffDNA in the maternal bloodstream has enabled clinical implementation of non-invasive prenatal diagnosis (NIPD) for monogenic disorders. Detection of paternally inherited and de novo mutations is relatively straightforward, and several methods have been developed for clinical use, including quantitative polymerase chain reaction (qPCR), and PCR followed by restriction enzyme digest (PCR-RED) or next-generation sequencing (NGS). A greater challenge has been in the detection of maternally inherited variants owing to the high background of maternal cell-free DNA (cfDNA). Molecular counting techniques have been developed to measure subtle changes in allele frequency. For instance, relative haplotype dosage analysis (RHDO), which uses single nucleotide polymorphisms (SNPs) for phasing of high- and low-risk alleles, is clinically available for several monogenic disorders. A major drawback is that RHDO requires samples from both parents and an affected or unaffected proband, therefore alternative methods, such as proband-free RHDO and relative mutation dosage (RMD), are being investigated. cffDNA was thought to exist only as short fragments (<500 bp); however, long-read sequencing technologies have recently revealed a range of sizes up to ∼23 kb. cffDNA also carries a specific placental epigenetic mark, and so fragmentomics and epigenetics are of interest for targeted enrichment of cffDNA. Cell-based NIPD approaches are also currently under investigation as a means to obtain a pure source of intact fetal genomic DNA. [ABSTRACT FROM AUTHOR]

Background: Prenatal exome sequencing (ES) for monogenic disorders in fetuses with structural anomalies increases diagnostic yield. In England there is a national trio ES service delivered from two laboratories. To minimise incidental findings and reduce the number of variants investigated, analysis uses a panel of 1205 genes where pathogenic variants may cause abnormalities presenting prenatally. Here we review our laboratory's early experience developing and delivering ES to identify challenges in interpretation and reporting and inform service development. Methods: A retrospective laboratory records review from 01.04.2020 to 31.05.2021. Results: Twenty‐four of 116 completed cases were identified as challenging including 13 resulting in difficulties in analysis and reporting, nine where trio inheritance filtering would have missed the diagnosis, and two with no prenatal diagnosis; one due to inadequate pipeline sensitivity, the other because the gene was not on the panel. Two cases with copy number variants identified were not detectable by microarray. Conclusions: Variant interpretation requires close communication between referring clinicians, with occasional additional examination of the fetus or parents and communication of evolving phenotypes. Inheritance filtering misses ∼5% of diagnoses. Panel analysis reduces but does not exclude incidental findings. Regular review of published literature is required to identify new reports that may aid classification. Key points: What's already known about this topic? Prenatal exome sequencing (ES) for monogenic disorders in fetuses with structural anomalies is known to increase diagnostic yieldDiagnostic prenatal ES services are being embedded into clinical practice internationally What does this study add? This study identifies challenges encountered running a diagnostic prenatal ES service including those in variant interpretation and reporting, incidental findings and ethical issuesIt demonstrates that solely relying on trio inheritance filtering will miss ∼5% of diagnosesClose communication between scientists and referring clinicians is essential to identify evolving phenotypesRegular review of published literature is required to identify new reports that may alter variant classification [ABSTRACT FROM AUTHOR]

Objective: We conducted a survey‐based discrete‐choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries. Methods: Five test attributes were identified as being important for decision‐making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis. Results: Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country‐specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs. Conclusion: Most women want maximum information from prenatal genomic tests, but our findings highlight country‐based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable. Key points: What's already known about this topic?Prenatal genome‐wide sequencing approaches increase diagnostic yield but also the chance of identifying uncertain findings.It is unclear which test features drive women's preferences for prenatal genomic testing. What does this study add?The findings add to our understanding of whether and how attitudes differ across countries with varying cultures and healthcare services.This work highlights the importance of guidelines tailored to individual countries as well as pre‐test counseling that identifies the personal values and preferences of patients. [ABSTRACT FROM AUTHOR]

The research and clinical use of genome-wide sequencing for prenatal diagnosis of fetuses at risk for genetic disorders have rapidly increased in recent years. Current data indicate that the diagnostic rate is comparable and for certain indications higher than that of standard testing by karyotype and chromosomal microarray. Responsible clinical implementation and diagnostic use of prenatal sequencing depends on standardized laboratory practices and detailed pre-test and post-test counseling. This Updated Position Statement on behalf of the International Society for Prenatal Diagnosis recommends best practices for the clinical use of prenatal exome and genome sequencing from an international perspective. We include several new points for consideration by researchers and clinical service and laboratory providers. [ABSTRACT FROM AUTHOR]

Objectives: Prenatal exome sequencing (pES) for the diagnosis of fetal abnormalities is being introduced more widely in clinical practice. Here we explore parents' and professionals' views and experiences of pES, to identify perceived benefits, concerns, and support needs. Methods: Semi‐structured interviews were conducted with 11 parents and 20 health professionals (fetal medicine and clinical genetics) with experience of rapid pES prior to implementation in the English National Health Service. Interviews were transcribed verbatim and analysed thematically. Results: Parents and professionals were largely positive about pES, emphasising clinical and psychosocial benefits of a timely, definitive diagnosis in pregnancy. Concerns included parental anxiety related to the timing of pES results or uncertain findings, a need for guidelines for case selection and reporting, and ensuring sufficient capacity for counselling, phenotyping and variant interpretation. Professionals were concerned non‐genetics professionals may not be equipped to counsel parents on the complexities of pES. Conclusion: These findings highlight important issues for clinical implementation of pES. Expert counselling is required to enable parents to make informed decisions during a stressful time. To achieve this, professionals need further education and training, and fetal medicine and genetics services must work closely together to ensure parental understanding and appropriate support. Key points: What's already known about this topic? Prenatal exome sequencing (pES) increases genetic diagnoses in structurally abnormal fetuses.Health professionals (HPs) anticipate clinical utility from pES and recognise the need for expert counselling, informed consent and clinical guidelines. What does this study add? UK HPs delivering rapid pES felt positive about pES but worried about variants of uncertain significance and incidental findings (IFs).Parents welcomed the offer of pES, provided they had sufficient time, support and opportunities to ask questions, both for decision making and after receiving results.Recommendations for successful clinical implementation of pES based on parent and HP feedback include improved multidisciplinary working, increased parental support and HP education. [ABSTRACT FROM AUTHOR]

Objectives: We conducted a systematic review and meta‐analysis to determine the diagnostic yield of exome sequencing (ES) for prenatal diagnosis of fetal structural anomalies, where karyotype/chromosomal microarray (CMA) is normal. Methods: Following electronic searches of four databases, we included studies with ≥10 structurally abnormal fetuses undergoing ES or whole genome sequencing. The incremental diagnostic yield of ES over CMA/karyotype was calculated and pooled in a meta‐analysis. Sub‐group analyses investigated effects of case selection and fetal phenotype on diagnostic yield. Results: We identified 72 reports from 66 studies, representing 4350 fetuses. The pooled incremental yield of ES was 31% (95% confidence interval (CI) 26%–36%, p < 0.0001). Diagnostic yield was significantly higher for cases pre‐selected for likelihood of monogenic aetiology compared to unselected cases (42% vs. 15%, p < 0.0001). Diagnostic yield differed significantly between phenotypic sub‐groups, ranging from 53% (95% CI 42%–63%, p < 0.0001) for isolated skeletal abnormalities, to 2% (95% CI 0%–5%, p = 0.04) for isolated increased nuchal translucency. Conclusion: Prenatal ES provides a diagnosis in an additional 31% of structurally abnormal fetuses when CMA/karyotype is non‐diagnostic. The expected diagnostic yield depends on the body system(s) affected and can be optimised by pre‐selection of cases following multi‐disciplinary review to determine that a monogenic cause is likely. Key points: What's already known about this topic? Prenatal exome sequencing (ES) increases genetic diagnoses in fetuses with structural abnormalities and a normal karyotype and chromosomal microarray.Published diagnostic yields from ES are varied and may be influenced by study size, case selection and fetal phenotype. What does this study add? This study provides a comprehensive systematic review of the literature to date and investigates the diagnostic yield of ES for a range of isolated system anomalies, to support clinical decision‐making on how to offer prenatal ES. [ABSTRACT FROM AUTHOR]

Objective: To identify what online patient information (presented in English) is available to parents about prenatal microarray (CMA) and exome sequencing (ES), and evaluate its content, quality, and readability. Method: Systematic searches (Google and Bing) were conducted, and websites were categorised according to their purpose. Websites categorised as patient information were included if they were: in English, directed at patients, or were a text, video, or online version of an information leaflet. Author‐developed content checklists, the DISCERN Genetics tool, and readability tests (the Flesch Reading Ease Score, the Gunning Fog Index, and the Simple Measure of Gobbledygook Index) were then used to assess those sources of patient information. Results: Of the 665 websites screened, 18 met the criteria. A further 8 sources were found through a targeted search of professional organisations, resulting in 26 sources available for further evaluation. In general, this was found to be low in quality, omitted details recommended by national or international guidance, and was written at a level too advanced for average readers. Conclusion: Improvements should be made to the content, quality, and readability of online information so that it both reinforces and complements the discussions between parents and clinicians about testing options during pregnancy. Key points: What's already known about this topic? The Internet is an important source of information for parents during pregnancyLittle is known about the availability and standard of online information about newer prenatal genetic tests like chromosomal microarray (CMA) and prenatal exome sequencing (ES) What does this study add?Our results revealed limited online information aimed at parents about CMA and ESThe information we did identify was lacking the details recommended by professional guidelines, had low quality scores, and was written at an advanced levelImprovements to online information for parents are needed to support informed decision‐making regarding prenatal genetic tests [ABSTRACT FROM AUTHOR]

Non‐invasive prenatal testing (NIPT) based on analysis of cell free DNA circulating in the maternal plasma has been available clinically to screen for chromosomal abnormalities since 2011. There is significant evidence to suggest that NIPT has revolutionised prenatal screening for the common trisomies 13, 18, and 21. However, the evidence in favour of its extended use to screen for conditions other than these trisomies remains a topic of debate with no national or international organisation supporting clinical implementation for these indications. In the debate presented here – "Expanded NIPT that includes conditions other than trisomies 13, 18, and 21 should be offered" – we will see the pros and cons of screening for a wider range of chromosomal problems. The discussion presented swung the vote from 65% in favour and 35% against before the arguments were voiced to 41% in favour and 59% against. This significant swing in the vote indicates that the majority of our community feel more evidence is required before clinical implementation of extended NIPT. Key Points: What's already known about the topic? Non‐invasive prenatal testing (NIPT) is recognised as a highly efficient screening test for trisomy 21, trisomy 18, and trisomy 13 which has been implemented worldwide.The sensitivity, specificity, and positive predictive value (PPV) of cell free DNA for these three trisomies and sex chromosome anomalies are well described in the peer‐reviewed medical literature, but there is less evidence on performance or clinical utility when screening for other chromosomal anomalies or rare autosomal trisomies.There remains debate on whether expanded NIPT that includes conditions other than trisomies 13,18 and 21 should be offered. What does this study add? This report summarises the debate presented during the International Society of Prenatal Diagnosis virtual educational series in October 2020.Through the debate, the benefits, limitations, and challenges of offering expanded NIPT that includes screening for microdeletions, sex chromosome anomalies and rare autosomal trisomies was reviewed and discussed.At the end of the debate the audience was divided but the majority did not agree with offering expanded NIPT. [ABSTRACT FROM AUTHOR]

Genome sequencing is increasingly being used to aid genetic diagnosis in fetuses with structural abnormalities detected on ultrasound examination. However, with clinical exome and genome sequencing, there is potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing, but of potential medical value for patient care. In the postnatal setting, the American College of Medical Genetics and Genomics (ACMG) has clear guidelines that state that when offering sequencing, secondary findings should be reported in 59 genes for which ACMG consider there is a clinical evidence that pathogenic variants may result in disease that might be prevented or treated, with the option to opt out of receiving this information. However, these guidelines specifically exclude prenatal sequencing. Here, we report the debate on whether or not pathogenic findings in these 59 genes should or should not be reported in the prenatal setting. Although more were in favour of reporting before the debate, there was no significant consensus from the audience. After the debate there was a swing toward not reporting, but a slim majority (55%) remained in favour, indicating that this is an area requiring further research and the development of evidence-based guidelines applicable to prenatal proband and trio sequencing. [ABSTRACT FROM AUTHOR]

Genome sequencing is increasingly being used to aid genetic diagnosis in fetuses with structural abnormalities detected on ultrasound examination. However, with clinical exome and genome sequencing, there is potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing, but of potential medical value for patient care. In the postnatal setting, the American College of Medical Genetics and Genomics (ACMG) has clear guidelines that state that when offering sequencing, secondary findings should be reported in 59 genes for which ACMG consider there is a clinical evidence that pathogenic variants may result in disease that might be prevented or treated, with the option to opt out of receiving this information. However, these guidelines specifically exclude prenatal sequencing. Here, we report the debate on whether or not pathogenic findings in these 59 genes should or should not be reported in the prenatal setting. Although more were in favour of reporting before the debate, there was no significant consensus from the audience. After the debate there was a swing toward not reporting, but a slim majority (55%) remained in favour, indicating that this is an area requiring further research and the development of evidence‐based guidelines applicable to prenatal proband and trio sequencing. [ABSTRACT FROM AUTHOR]

Background: Tests in pregnancy such as chromosomal microarray analysis and exome sequencing are increasing diagnostic yield for fetal structural anomalies, but have greater potential to result in uncertain findings. This systematic review investigated the experiences of prospective parents about receiving uncertain results from these tests.Methods: A systematic search of three electronic databases was conducted. Data extraction was performed for studies that met the eligibility and quality criteria. Results were synthesised following the principles of thematic analysis.Results: Fourteen studies (10 qualitative, 4 quantitative) were included. Findings were grouped into three overarching themes. Sources of uncertainty included the testing procedure, the diagnosis and prognosis, and health professionals' own uncertainty. The clinical impact of the uncertainty included parents struggling to make clinical decisions with the information available, the emotional impact included decisional-regret, shock, worry and feeling overwhelmed. To manage the uncertainty, parents sought support from healthcare professionals, friends, family, the internet and other parents as well as remaining hopeful.Conclusions: Prospective parents experience a myriad of uncertainties in the prenatal setting, which must be handled sensitively. Future research should explore optimal ways of managing uncertainty to minimise harm. Recommendations are made for discussing uncertainty during pre- and post-test counseling. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the diagnostic yield of noninvasive prenatal diagnosis (NIPD) for FGFR3-related skeletal dysplasias and assess the accuracy of referrals based on sonographic findings to inform guidelines for referral.Methods: We retrospectively reviewed laboratory and referral records from 2012 to 2018 to ascertain all NIPD tests performed using our next generation sequencing panel to detect FGFR3 mutations. We calculated the diagnostic yield of the test overall and when sub-divided according to the phenotypic features identified on ultrasound before testing. Pregnancy outcomes were ascertained wherever possible from referring centers.Results: Of 335 tests, 261 were referred because of sonographic findings, of which 80 (31.3%) had a mutation. The diagnostic yield when short limbs were the only abnormal sonographic feature reported was 17.9% (30/168), increasing to 48.9% (23/47) in the presence of one, and 82.6% (19/23) in the presence of two or more characteristic features in addition to short limbs.Conclusions: Accurate sonographic phenotyping can maximise the diagnostic yield of NIPD in fetuses suspected to have FGFR3-related skeletal dysplasias. We suggest that clear guidelines for referral are necessary to increase benefits, decrease costs by preventing unnecessary NIPD, and potentially allow first-line broader spectrum testing for fetuses where the aetiology may be more heterogeneous. [ABSTRACT FROM AUTHOR]

Background: Consent rates for postmortem (PM) examination in the perinatal and paediatric setting have dropped significantly in the United Kingdom, the United States, and the Western Europe. We explored the factors that act as facilitators or barriers to consent and identified processes and practices that support parental decision-making.Methods: A qualitative study conducted with bereaved parents, parent advocates, and health care professionals in the United Kingdom. Analysis was conducted on 439 free-tect comments within a cross-sectional survey, interviews with a subset of 20 survey respondents and 25 health professionals, and a focus group with five parent advocates.Results: Three broad parental decision-making groups were identified: 1, "Not open to postmortem examination"; 2, "Consent regardless of concerns"; and 3, "Initially undecided." Decisional drivers that were particularly important for this "undecided" group were "the initial approach," "adjustment and deliberation," "detailed discussion about the procedure," and "formal consent." The way in which these were managed by health care staff significantly impacted whether those parents' consented to PM, particularly for those who are ambivalent about the procedure.Conclusions: We propose a set of recommendations to improve the way PM counselling and consent is managed. Adopting such measures is likely to lead to improved family experience and more consistent and high-quality discussion regarding PM. [ABSTRACT FROM AUTHOR]

Objectives Genome sequencing is poised to be incorporated into clinical care for diagnoses of rare diseases and some cancers in many parts of the world. Healthcare professionals are key stakeholders in the clinical delivery of genome sequencing-based services. Our aim was to explore views of healthcare professionals with experience of offering genome sequencing via the 100 000 Genomes Project. Design Interview study using thematic analysis. Setting Four National Health Service hospitals in London. Participants Twenty-three healthcare professionals (five genetic clinicians and eight non-genetic clinicians (all consultants), and 10 ‘consenters’ from a range of backgrounds) involved in identifying or consenting patients for the 100 000 Genomes Project. Results Most participants expressed positive attitudes towards genome sequencing in terms of improved ability to diagnose rare diseases, but many also expressed concerns, with some believing its superiority over exome sequencing had not yet been demonstrated, or worrying that non-genetic clinicians are inadequately prepared to discuss genome sequencing results with patients. Several emphasised additional evidence about utility of genome sequencing in terms of both main and secondary findings is needed. Most felt non-genetic clinicians could support patients during consent, as long as they have appropriate training and support from genetic teams. Many stated genetics experts will play a vital role in training and supporting non-genetic clinicians in variant interpretation and results delivery, particularly for more complex cases. Conclusions Healthcare professionals responsible for delivering clinical genome sequencing have largely positive views about the potential for genome sequencing to improve diagnostic yield, but also significant concerns about practical aspects of offering these tests. Non-genetic clinicians delivering genome sequencing require guidance and support. Additional empirical evidence is needed to inform policy and practice, including how genome compares to exome sequencing; utility of secondary findings; training, in particular of non-genetic health professionals; and mechanisms whereby genetics teams can offer appropriate support to their non-genetics colleagues. [ABSTRACT FROM AUTHOR]

Genome sequencing (GS) is increasingly being used to diagnose rare diseases in paediatric patients; however, no measures exist to evaluate their knowledge of this technology. We aimed to develop a robust measure of knowledge of GS (the kids‐KOGS') suitable for use in the paediatric setting as well as for general public education. The target age was 11 to 15 year olds. An iterative process involving six sequential stages was conducted to develop a set of draft true/false items. These were then administered to 539 target‐age school pupils (mean 12.8; SD ± 1.3), from the United Kingdom. Item‐response theory was used to confirm the psychometric suitability of the candidate items. None of the Items was identified as misfits. All 10 items performed well under the two‐parameter logistic model. The internal consistency of the test was 0.84 (Cronbach alpha value) indicating excellent reliability. The mean kids‐KOGS score in the sample overall was 4.24 (SD; 2.49), where 0 = low knowledge and 10 = high knowledge. Age was positively associated with score in a multivariate linear regression. The kids‐KOGS is a short and reliable tool that can be used by researchers and healthcare professionals offering GS to paediatric patients. Further validation in a clinical setting is required. [ABSTRACT FROM AUTHOR]

This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved. [ABSTRACT FROM AUTHOR]

Skeletal dysplasias are a heterogeneous group of conditions, many of which present unexpectedly in the prenatal period with a variety of ultrasound findings. Accurate prenatal diagnosis can now be facilitated using exome sequencing approaches, but in order to interpret results, accurate and detailed phenotyping is required. Here, we describe the sonographic approach to the prenatal diagnosis of skeletal abnormalities and illustrate how taking a systematic approach can facilitate diagnosis. [ABSTRACT FROM AUTHOR]

Objective: To determine the additional yield from autopsy following prenatal ultrasound and post-mortem magnetic resonance imaging (PMMR) for structural abnormalities.Method: PMMR was performed on consecutive fetuses over a 6-year period. Prenatal ultrasound and PMMR findings were categorised as concordant, partially concordant or discordant findings. The yield of new and clinically significant information from autopsy was assessed. Diagnostic accuracies for both modalities were calculated, using autopsy as reference standard.Results: Our study consisted of 81 fetuses. PMMR and prenatal ultrasound findings were concordant in 44/81 (54.3%), partially concordant in 26/81 (32.1%) and discordant in 11/81 (13.6%) cases. In 19/81 cases (23%), autopsy provided additional information, which appeared clinically significant in 12 cases. In 10 of those 12 cases, there was discordance between PMMR and ultrasound. In only 2 of 44 cases where ultrasound and PMMR were concordant, did autopsy provide clinically significant information. Diagnostic accuracy rates for ultrasound were sensitivity of 76.8% (66.6%, 84.6%), specificity of 92.5% (88.9%, 95.0%). For PMMR the sensitivity was 79.0% (68.9%, 86.5%), specificity 97.9% (95.5%, 99.0%). PMMR had a significantly higher concordance rate with autopsy than ultrasound (89.0 vs 93.8%; P < .001).Conclusion: Where PMMR and ultrasound are concordant, there is little additional yield from autopsy. [ABSTRACT FROM AUTHOR]

Objective: To ensure accurate and appropriate reporting of non-invasive prenatal testing (NIPT) results, the standard of testing should be measured and monitored by participation in external quality assessment (EQA) schemes. The findings from international pilot EQAs for NIPT for the common trisomies are presented.Methods: In the first pilot, three EQA providers used artificially manufactured reference materials to deliver an EQA for NIPT. The second pilot used clinically collected maternal plasma samples. The testing and reporting for aneuploidy status was performed by participating laboratories using routine procedures. Reports were assessed against peer ratified criteria and EQA scores were returned to participants.Results: Forty laboratories participated in the first. Genotyping accuracy was high; four laboratories reported a critical genotyping error (10%) and two reported partial results. Eighty seven laboratories participated in the second pilot using maternal plasma, two reporting a critical genotyping error (2.3%). For both rounds, report content was variable with key information frequently omitted or difficult to identify within the report.Conclusions: We have successfully delivered an international pilot EQA for NIPT. When compared with currently available manufactured materials, EQA for NIPT was best performed using clinically collected maternal plasma. Work is required to define and improve the standard of reporting. [ABSTRACT FROM AUTHOR]

Background: Perinatal and paediatric autopsy rates are at historically low levels with declining uptake due to dislike of the invasiveness of the procedure, and religious objections particularly amongst Muslim and Jewish parents. Less invasive methods of autopsy including imaging with and without tissue sampling have been shown to be feasible alternatives. We sought to investigate attitudes including religious permissibility and potential uptake amongst members of the Muslim and Jewish communities in the United Kingdom. Methods: Semi-structured interviews with religious and faith-based authorities (n = 16) and bereaved parents from the Jewish community (n = 3) as well as 10 focus groups with community members (60 Muslim participants and 16 Jewish participants) were conducted. Data were analysed using thematic analysis to identify key themes. Findings: Muslim and Jewish religious and faith-based authorities agreed that non-invasive autopsy with imaging was religiously permissible because it did not require incisions or interference with the body. A minimally invasive approach was less acceptable as it still required incisions to the body, although in those circumstances where it was required by law it was more acceptable than a full autopsy. During focus group discussions with community members, the majority of participants indicated they would potentially consent to a non-invasive autopsy if the body could be returned for burial within 24 hours, or if a family had experienced multiple fetal/pregnancy losses and the information gained might be useful in future pregnancies. Minimally invasive autopsy was less acceptable but around half of participants might consent if a non-invasive autopsy was not suitable, with the exception of the Jewish Haredi community who unanimously stated they would decline this alternative. Conclusions: Our research suggests less invasive autopsy offers a viable alternative to many Muslim and Jewish parents in the UK who currently decline a full autopsy. The findings may be of importance to other countries with significant Muslim and/or Jewish communities as well as to other religious communities where concerns around autopsy exist. Awareness-raising amongst religious leaders and community members will be important if these methods become routinely available. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To assess health professionals' and coroners' attitudes towards non-minimally and minimally invasive autopsy in the perinatal and paediatric setting.Methods: A qualitative study using semistructured interviews. Data were analysed thematically.Results: Twenty-five health professionals (including perinatal/paediatric pathologists and anatomical pathology technologists, obstetricians, fetal medicine consultants and bereavement midwives, intensive care consultants and family liaison nurses, a consultant neonatologist and a paediatric radiologist) and four coroners participated. Participants viewed less invasive methods of autopsy as a positive development in prenatal and paediatric care that could increase autopsy rates. Several procedural and psychological benefits were highlighted including improved diagnostic accuracy in some circumstances, potential for faster turnaround times, parental familiarity with imaging and laparoscopic approaches, and benefits to parents and faith groups who object to invasive approaches. Concerns around the limitations of the technology such not reaching the same levels of certainty as full autopsy, unsuitability of imaging in certain circumstances, the potential for missing a diagnosis (or misdiagnosis) and de-skilling the workforce were identified. Finally, a number of implementation issues were raised including skills and training requirements for pathologists and radiologists, access to scanning equipment, required computational infrastructure, need for a multidisciplinary approach to interpret results, cost implications, equity of access and acceptance from health professionals and hospital managers.Conclusion: Health professionals and coroners viewed less invasive autopsy as a positive development in perinatal and paediatric care. However, to inform implementation a detailed health economic analysis and further exploration of parental views, particularly in different religious groups, are required. [ABSTRACT FROM AUTHOR]

Non-invasive prenatal testing (NIPT), based on analysis of cell-free foetal DNA, is rapidly becoming a preferred method to screen for chromosomal aneuploidy with the technology now available in over 90 countries. This review provides an up-to-date discussion of the key clinical, social and ethical implications associated with this revolutionary technology. Stakeholders are positive about a test that is highly accurate, safe, can be perfomed early in pregnancy, identifies affected pregnancies that might otherwise have been missed and reduces the need for invasive testing. Nevertheless, professional societies currently recommend it as an advanced screening test due to the low false positive rate (FPR). Despite the practical and psychological benefits, a number of concerns have been raised which warrant attention. These include the potential for routinisation of testing and subsequent impact on informed decision-making, an "easy" blood test inadvertently contributing to women feeling pressured to take the test, fears NIPT will lead to less tolerance and support for those living with Down syndrome and the heightened expectation of having "perfect babies". These issues can be addressed to some extent through clinician education, patient information and establishing national and international consensus in the development of comprehensive and regularly updated guidelines. As the number of conditions we are able to test for non-invasively expands it will be increasingly important to ensure pre-test counselling can be delivered effectively supported by knowledgeable healthcare professionals. [ABSTRACT FROM AUTHOR]

Noninvasive prenatal testing (NIPT) using cell-free DNA (cfDNA) from maternal serum has been clinically available since 2011. This technology has revolutionized our ability to screen for the common aneuploidies trisomy 21 (Down syndrome), trisomy 18, and trisomy 13. More recently, clinical laboratories have offered screening for other chromosome abnormalities including sex chromosome abnormalities and copy number variants (CNV) without little published data on the sensitivity, specificity, and positive predictive value. In this debate, the pros and cons of performing prenatal screening via cfDNA for all chromosome abnormalities is discussed. At the time of the debate in 2017, the general consensus was that the literature does not yet support using this technology to screen for all chromosome abnormalities and that education is key for both providers and the patients so that the decision-making process is as informed as possible. [ABSTRACT FROM AUTHOR]

Prenatal genetic diagnosis provides information for pregnancy and perinatal decision-making and management. In several small series, prenatal whole exome sequencing (WES) approaches have identified genetic diagnoses when conventional tests (karyotype and microarray) were not diagnostic. Here, we review published prenatal WES studies and recent conference abstracts. Thirty-one studies were identified, with diagnostic rates in series of five or more fetuses varying between 6.2% and 80%. Differences in inclusion criteria and trio versus singleton approaches to sequencing largely account for the wide range of diagnostic rates. The data suggest that diagnostic yields will be greater in fetuses with multiple anomalies or in cases preselected following genetic review. Beyond its ability to improve diagnostic rates, we explore the potential of WES to improve understanding of prenatal presentations of genetic disorders and lethal fetal syndromes. We discuss prenatal phenotyping limitations, counselling challenges regarding variants of uncertain significance, incidental and secondary findings, and technical problems in WES. We review the practical, ethical, social and economic issues that must be considered before prenatal WES could become part of routine testing. Finally, we reflect upon the potential future of prenatal genetic diagnosis, including a move towards whole genome sequencing and non-invasive whole exome and whole genome testing. © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Implementation of noninvasive prenatal testing (NIPT) as a highly accurate aneuploidy screening test has raised questions around whether the high uptake may result in more terminations of pregnancies and fewer births of children with Down syndrome (DS). Aim: The aim of the study was to investigate the impact of NIPT on termination and live birth rates for DS. Methods: Literature reporting pregnancy outcomes following NIPT was reviewed. Termination rates were calculated for women with a high‐risk NIPT result for DS. Two audits of pregnancy outcomes where NIPT indicated DS were conducted in the United Kingdom and Singapore. Results: Fourteen studies from the United States, Asia, Europe, and the United Kingdom were included in the review. Live births of children with DS were reported in 8 studies. Termination rates following NIPT were unchanged or decreased when compared to termination rates prior to the introduction of NIPT. Audits found 15 of 43 women in the United Kingdom and 2 of 6 in Singapore continued pregnancies following a high‐risk NIPT result. Conclusions: Termination rates following the detection of DS by NIPT are unchanged or decreased compared to historical termination rates. Impact on live birth rates may be minimal in settings where termination rates fall. Population‐based studies are required to determine the true impact. [ABSTRACT FROM AUTHOR]

Background: Implementation of noninvasive prenatal testing (NIPT) as a highly accurate aneuploidy screening test has raised questions around whether the high uptake may result in more terminations of pregnancies and fewer births of children with Down syndrome (DS).Aim: The aim of the study was to investigate the impact of NIPT on termination and live birth rates for DS.Methods: Literature reporting pregnancy outcomes following NIPT was reviewed. Termination rates were calculated for women with a high-risk NIPT result for DS. Two audits of pregnancy outcomes where NIPT indicated DS were conducted in the United Kingdom and Singapore.Results: Fourteen studies from the United States, Asia, Europe, and the United Kingdom were included in the review. Live births of children with DS were reported in 8 studies. Termination rates following NIPT were unchanged or decreased when compared to termination rates prior to the introduction of NIPT. Audits found 15 of 43 women in the United Kingdom and 2 of 6 in Singapore continued pregnancies following a high-risk NIPT result.Conclusions: Termination rates following the detection of DS by NIPT are unchanged or decreased compared to historical termination rates. Impact on live birth rates may be minimal in settings where termination rates fall. Population-based studies are required to determine the true impact. [ABSTRACT FROM AUTHOR]