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Objective: This study aimed to determine the incremental yield of prenatal exome sequencing over chromosomal microarray or G-banding karyotype in fetuses with: (1) intrauterine growth restriction related to placental insufficiency or (2) short long bones, in isolated and nonisolated instances for both scenarios., Data Sources: Data were collected via electronic searches for relevant citations from January 2010 to April 10, 2022 in MEDLINE, Embase, Web of Science, and Cochrane, and using relevant bibliographies and data generated in-house., Study Eligibility Criteria: Included were prospective or retrospective cohort studies and/or case series with: (1) n>5 cases of short long bones and/or intrauterine growth restriction undergoing prenatal sequencing with a clearly defined phenotype including assessment of placental function; (2) testing based on prenatal phenotype only; (3) a nondiagnostic chromosomal microarray/karyotype; and (4) known results of genetic testing., Methods: Incremental yield was calculated for each study and as a pooled value for the aforementioned groups using a random-effects model. Results were displayed in forest plots with 95% confidence intervals. Heterogeneity was assessed statistically using Higgins' I 2 . Publication bias was assessed graphically using funnel plots. Quality assessment was performed using modified Standards for Reporting of Diagnostic Accuracy criteria (International Prospective Register of Systematic Reviews registration number CRD42022324680)., Results: Nineteen studies were included (n=452 cases). The apparent incremental yields with prenatal sequencing were: (1) 4% (95% confidence interval, -5.0 to 12; I 2 =0%) in isolated intrauterine growth restriction with evidence of placental insufficiency, (2) 30% (95% confidence interval, 13-47; I 2 =1%) in intrauterine growth restriction with additional structural anomalies, (3) 48% (95% confidence interval, 26-70; I 2 =73%) in isolated short long bones, and (4) 68% (95% confidence interval, 58-77; I 2 =51%) in short long bones with additional skeletal anomalies. Of the 37 short long bone cases with a diagnosis, 32 had a skeletal dysplasia, with thanatophoric dysplasia and osteogenesis imperfecta being the most common (both 21.6% [n=8/37]). In fetuses with short long bones and additional skeletal features, osteogenesis imperfecta was the most common diagnosis (28% [n=57/204]). Where documented, the inheritance patterns were de novo in 75.4% (n=150) of cases., Conclusion: Prenatal sequencing adds substantially to incremental yield over chromosomal microarray in fetuses with short long bones or multisystem intrauterine growth restriction. Robust studies are required to assess the utility of fetal sequencing in isolated intrauterine growth restriction with evidence of placental insufficiency, which cannot be recommended on the basis of current evidence., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Osteogenesis imperfecta (OI) is a rare genetic condition characterised by increased bone fragility. Recurrent fractures, pain and fatigue have a considerable impact on many aspects of the life of a person affected with OI and their families., Objective: To improve our understanding of the impact of OI on the daily lives of individuals and families and consider how the condition is managed so that support needs can be better addressed., Methods: Semi-structured qualitative interviews (n = 56) were conducted with adults affected with OI, with (n = 9) and without children (n = 8), parents of children affected with OI (n = 8), health professionals (n = 29) and patient advocates (n = 2). Interviews were digitally recorded, transcribed verbatim and analysed using thematic analysis., Results: Three overarching themes are described: OI is not just a physical condition, parenting and family functioning and managing the condition. Fractures, chronic pain and tiredness impact on daily life and emotional well-being. For parents with OI, pain, tiredness and mobility issues can limit interactions and activities with their children. Specialist paediatric health services for OI were highly valued. The need for more emotional support and improved coordination of adult health services was highlighted., Conclusions: Our findings allow a better understanding of the day-to-day experiences of individuals and families affected with OI. Supporting emotional well-being needs greater attention from policy makers and researchers. Improvements to the coordination of health services for adults with OI are needed and an in-depth exploration of young people's support needs is warranted with research focused on support through the teenage years., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to assess decisions, attitudes, and understanding of participants (patients, parents, relatives) having genome sequencing for rare disease diagnosis., Methods: This study involved a cross-sectional observational survey with participants in the 100,000 Genomes Project., Results: Survey response rate was 51% (504/978). Most participants self-reported that they had decided to undergo genome sequencing (94%) and that this was an informed decision (84%) with low decisional conflict (95%). Most self-reported that they had chosen to receive additional findings (88%) and that this was an informed decision (89%) with low decisional conflict (95%). Participants were motivated more by the desire to help others via research than by the belief it would help them obtain a diagnosis (Z = 14.23, P = 5.75 × 10 -46 ), although both motivations were high. Concerns were relatively few but, where expressed, were more about the potential psychological impact of results than data sharing/access (Z = 9.61, P = 7.65 × 10 -22 ). Concerns were higher among male, Asian or Asian British, and more religious participants. General and context-specific understanding of genome sequencing were both moderately high (means 5.2/9.0 and 22.5/28.0, respectively)., Conclusion: These findings are useful to inform consent guidelines and clinical implementation of genome sequencing., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

Unexpected fetal abnormalities detected through ultrasound scanning in pregnancy may have a monogenic aetiology but are difficult to diagnose. Next generation sequencing now enables us to sequence fetal exomes, providing increased resolution and broader diagnostic capability compared to traditional cytogenetic prenatal tests, improving the yield and accuracy of diagnoses and allowing better counselling for expectant parents. Here we review published studies of exome sequencing (ES) for prenatal diagnosis over the last 5 years and address important questions for its clinical implementation, including clinical utility, which groups benefit most, and practical and ethical challenges for interpreting and reporting results. We observe that fetal ES substantially improves diagnostic yield relative to cytogenetic techniques. However, diagnostic rates vary widely between studies, largely attributable to differences in case selection. Recently several large studies report variations in diagnostic yield between phenotypic groups, with fetuses with multisystem abnormalities most likely to receive a diagnosis from fetal ES. Challenges for prenatal ES include the limitations of ultrasound-based fetal phenotyping, the need for rapid return of results in pregnancy, and technical limitations compared to whole genome sequencing. We also consider ethical issues around potential secondary findings and variants of uncertain significance and the complex counselling needs these present. Prenatal ES is a valuable tool to diagnose fetal abnormalities and, as it is implemented in the clinic, more large-scale research will serve to further delineate its clinical utility, as well as generating new knowledge about fetal phenotypes and informing guidelines for case selection, reporting results and genetic counselling., (Copyright © 2019. Published by Elsevier Masson SAS.)

Purpose: Little is known about how health-care professionals communicate with patients about consenting to genome sequencing. We therefore examined what topics health-care professionals covered and what questions patients asked during consent conversations., Methods: Twenty-one genome sequencing consent appointments were audio recorded and analyzed. Participants were 35 individuals being invited to participate in the 100,000 Genomes Project (14 participants with rare diseases, 21 relatives), and 10 health-care professionals ("consenters")., Results: Two-thirds of participants' questions were substantive (e.g., genetics and inheritance); one-third administrative (e.g., filling in the consent form). Consenters usually (19/21) emphasized participant choice about secondary findings, but less often (13/21) emphasized the uncertainty about associated disease risks. Consenters primarily used passive statements and closed-ended, rather than open-ended, questions to invite participants' questions and concerns. In two appointments, one parent expressed negative or uncertain views about secondary findings, but after discussion with the other parent opted to receive them., Conclusion: Health-care professionals need to be prepared to answer patients' questions about genetics to facilitate genome sequencing consent. Health-care professionals' education also needs to address how to effectively listen and elicit each patient's questions and views, and how to discuss uncertainty around the disease risks associated with secondary findings.

Background: Fetal structural anomalies, which are detected by ultrasonography, have a range of genetic causes, including chromosomal aneuploidy, copy number variations (CNVs; which are detectable by chromosomal microarrays), and pathogenic sequence variants in developmental genes. Testing for aneuploidy and CNVs is routine during the investigation of fetal structural anomalies, but there is little information on the clinical usefulness of genome-wide next-generation sequencing in the prenatal setting. We therefore aimed to evaluate the proportion of fetuses with structural abnormalities that had identifiable variants in genes associated with developmental disorders when assessed with whole-exome sequencing (WES)., Methods: In this prospective cohort study, two groups in Birmingham and London recruited patients from 34 fetal medicine units in England and Scotland. We used whole-exome sequencing (WES) to evaluate the presence of genetic variants in developmental disorder genes (diagnostic genetic variants) in a cohort of fetuses with structural anomalies and samples from their parents, after exclusion of aneuploidy and large CNVs. Women were eligible for inclusion if they were undergoing invasive testing for identified nuchal translucency or structural anomalies in their fetus, as detected by ultrasound after 11 weeks of gestation. The partners of these women also had to consent to participate. Sequencing results were interpreted with a targeted virtual gene panel for developmental disorders that comprised 1628 genes. Genetic results related to fetal structural anomaly phenotypes were then validated and reported postnatally. The primary endpoint, which was assessed in all fetuses, was the detection of diagnostic genetic variants considered to have caused the fetal developmental anomaly., Findings: The cohort was recruited between Oct 22, 2014, and June 29, 2017, and clinical data were collected until March 31, 2018. After exclusion of fetuses with aneuploidy and CNVs, 610 fetuses with structural anomalies and 1202 matched parental samples (analysed as 596 fetus-parental trios, including two sets of twins, and 14 fetus-parent dyads) were analysed by WES. After bioinformatic filtering and prioritisation according to allele frequency and effect on protein and inheritance pattern, 321 genetic variants (representing 255 potential diagnoses) were selected as potentially pathogenic genetic variants (diagnostic genetic variants), and these variants were reviewed by a multidisciplinary clinical review panel. A diagnostic genetic variant was identified in 52 (8·5%; 95% CI 6·4-11·0) of 610 fetuses assessed and an additional 24 (3·9%) fetuses had a variant of uncertain significance that had potential clinical usefulness. Detection of diagnostic genetic variants enabled us to distinguish between syndromic and non-syndromic fetal anomalies (eg, congenital heart disease only vs a syndrome with congenital heart disease and learning disability). Diagnostic genetic variants were present in 22 (15·4%) of 143 fetuses with multisystem anomalies (ie, more than one fetal structural anomaly), nine (11·1%) of 81 fetuses with cardiac anomalies, and ten (15·4%) of 65 fetuses with skeletal anomalies; these phenotypes were most commonly associated with diagnostic variants. However, diagnostic genetic variants were least common in fetuses with isolated increased nuchal translucency (≥4·0 mm) in the first trimester (in three [3·2%] of 93 fetuses)., Interpretation: WES facilitates genetic diagnosis of fetal structural anomalies, which enables more accurate predictions of fetal prognosis and risk of recurrence in future pregnancies. However, the overall detection of diagnostic genetic variants in a prospectively ascertained cohort with a broad range of fetal structural anomalies is lower than that suggested by previous smaller-scale studies of fewer phenotypes. WES improved the identification of genetic disorders in fetuses with structural abnormalities; however, before clinical implementation, careful consideration should be given to case selection to maximise clinical usefulness., Funding: UK Department of Health and Social Care and The Wellcome Trust., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Unexpected fetal abnormalities occur in 2-5% of pregnancies. While traditional cytogenetic and microarray approaches achieve diagnosis in around 40% of cases, lack of diagnosis in others impedes parental counseling, informed decision making, and pregnancy management. Postnatally exome sequencing yields high diagnostic rates, but relies on careful phenotyping to interpret genotype results. Here we used a multidisciplinary approach to explore the utility of rapid fetal exome sequencing for prenatal diagnosis using skeletal dysplasias as an exemplar., Methods: Parents in pregnancies undergoing invasive testing because of sonographic fetal abnormalities, where multidisciplinary review considered skeletal dysplasia a likely etiology, were consented for exome trio sequencing (both parents and fetus). Variant interpretation focused on a virtual panel of 240 genes known to cause skeletal dysplasias., Results: Definitive molecular diagnosis was made in 13/16 (81%) cases. In some cases, fetal ultrasound findings alone were of sufficient severity for parents to opt for termination. In others, molecular diagnosis informed accurate prediction of outcome, improved parental counseling, and enabled parents to terminate or continue the pregnancy with certainty., Conclusion: Trio sequencing with expert multidisciplinary review for case selection and data interpretation yields timely, high diagnostic rates in fetuses presenting with unexpected skeletal abnormalities. This improves parental counseling and pregnancy management.

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.)

Sonographic diagnosis of fetal abnormalities is based on the recognition of sonographic patterns associated with structural abnormalities. Although diagnosis in some situations, such as neural tube defects, gastroschisis, and omphalocoele, can be straightforward, in many situations, the constellation of fetal abnormalities suggest an underlying chromosomal or genetic cause. In these situations, invasive testing is needed to provide the information required to make a definitive diagnosis, and thus accurately counsel parents. Since the identification of cell-free fetal DNA in maternal plasma, the potential for non-invasive prenatal diagnosis is increasingly becoming possible. In this chapter, the current role and future potential of non-invasive prenatal diagnosis, combined with new molecular techniques as an aid to sonographic diagnosis, will be discussed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Prenatal screening and diagnosis of Down syndrome and other major aneuploidies may be transformed following the identification of cell-free fetal DNA in maternal plasma at the end of the last millennium. Next generation sequencing has enabled the development of tests that accurately predict the presence of fetal trisomies by analysis of cell-free DNA in maternal blood from as early as 10 weeks of gestation. These tests are now widely available in the commercial sector but are yet to be implemented in publicly led health services. In this article we discuss the technical, social, and ethical challenges that these new tests bring., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Post-mortem MRI is a potential diagnostic alternative to conventional autopsy, but few large prospective studies have compared its accuracy with that of conventional autopsy. We assessed the accuracy of whole-body, post-mortem MRI for detection of major pathological lesions associated with death in a prospective cohort of fetuses and children., Methods: In this prospective validation study, we did pre-autopsy, post-mortem, whole-body MRI at 1·5 T in an unselected population of fetuses (≤24 weeks' or >24 weeks' gestation) and children (aged <16 years) at two UK centres in London between March 1, 2007 and Sept 30, 2011. With conventional autopsy as the diagnostic gold standard, we assessed MRI findings alone, or in conjunction with other minimally invasive post-mortem investigations (minimally invasive autopsy), for accuracy in detection of cause of death or major pathological abnormalities. A radiologist and pathologist who were masked to the autopsy findings indicated whether the minimally invasive autopsy would have been adequate. The primary outcome was concordance rate between minimally invasive and conventional autopsy., Findings: We analysed 400 cases, of which 277 (69%) were fetuses and 123 (31%) were children. Cause of death or major pathological lesion detected by minimally invasive autopsy was concordant with conventional autopsy in 357 (89·3%, 95% CI 85·8-91·9) cases: 175 (94·6%, 90·3-97·0) of 185 fetuses at 24 weeks' gestation or less, 88 (95·7%, 89·3-98·3) of 92 fetuses at more than 24 weeks' gestation, 34 (81·0%, 66·7-90·0) [corrected] of 42 newborns aged 1 month or younger, 45 (84·9%, 72·9-92·1) of 53 infants aged older than 1 month to 1 year or younger, and 15 (53·6%, 35·8-70·5) of 28 children aged older than 1 year to 16 years or younger. The dedicated radiologist or pathologist review of the minimally invasive autopsy showed that in 165 (41%) cases a full autopsy might not have been needed; in these cases, concordance between autopsy and minimally invasive autopsy was 99·4% (96·6-99·9)., Interpretation: Minimally invasive autopsy has accuracy similar to that of conventional autopsy for detection of cause of death or major pathological abnormality after death in fetuses, newborns, and infants, but was less accurate in older children. If undertaken jointly by pathologists and radiologists, minimally invasive autopsy could be an acceptable alternative to conventional autopsy in selected cases., Funding: Policy research Programme, Department of Health, UK., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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.)

Purpose: To compare the preferences of women and health professionals for key attributes of noninvasive prenatal diagnosis for Down syndrome relative to current invasive tests., Methods: A questionnaire incorporating a discrete choice experiment was used to obtain participants' stated preference for diagnostic tests that varied according to four attributes: accuracy, time of test, risk of miscarriage, and provision of information about Down syndrome only or Down syndrome and other conditions. Women and health professionals were recruited from five maternity services in England and a patient support group., Results: Questionnaires from 335 women and 181 health professionals were analyzed. Safe tests, conducted early in pregnancy, with high accuracy and information about Down syndrome and other conditions were preferred. The key attribute affecting women's preferences for testing was no risk of miscarriage, whereas for health professionals it was accuracy., Conclusions: Policies for implementing noninvasive prenatal diagnosis must consider the differences between women's and health professionals' preferences to ensure the needs of all stakeholders are met. Women's strong preference for tests with no risk of miscarriage demonstrates that consideration for safety of the fetus is paramount in decision making. Effective pretest counseling is therefore essential to ensure women understand the possible implications of results.

For over a decade, researchers have focused their attention on the development of non-invasive prenatal diagnosis tests based on cell-free fetal DNA circulating in maternal blood. With the possibility of earlier and safer testing, non-invasive prenatal diagnosis has the potential to bring many positive benefits to prenatal diagnosis. Non-invasive prenatal diagnosis for fetal sex determination for women who are carriers of sex-linked conditions is now firmly established in clinical practice. Other non-invasive prenatal diagnosis-based tests are set to follow, as future applications, such as the detection of single-gene disorders and chromosomal abnormalities, are now well within reach. Here, we review recent developments in non-invasive prenatal diagnosis for genetic conditions and chromosomal abnormalities, and provide an overview of research into ethical concerns, social issues and stakeholder view points., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Two new biomarkers, serum amyloid-P (SAP) and plasma C1-inhibitor protein are elevated in the maternal circulation of mothers carrying Down syndrome foetuses. Much emphasis of late\ has been put on the lack of translational tests being developed following the identification of new biomarkers. We have created a single-reaction-monitoring (SRM) tandem mass spectrometry-based assay for the quantitation of these biomarkers and compared these results with an in-house developed immunofluorescence-based technique (IF). This MS-based assay is a rapid 5 min test and a simple "one pot reaction," requiring only 5μl of plasma. To evaluate the potential of SRM-based quantitation in a clinical setting, SAP and C1-inhibitor were quantitated in 38 normal and Down syndrome affected pregnancies. Plasma SAP levels in the Down's group were significantly raised at 10-14 weeks (p<0.0015) and 14-20 weeks (p<0.0001). Plasma C1-inhibitor levels were also observed significantly elevated in the Down's group (10-14 weeks, p<0.0193, 14-20 weeks, p<0.0001). Analysis using the IF technique did not show any significant elevation of plasma SAP levels or C1-inhibitor levels. This rapid and sensitive assay demonstrates the potential of multiplexed tandem MS-based quantitation of proteins in chemical pathology labs and in a more cost-effective, accurate manner than conventionally used antibody methods., (Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.)

Using ProteinChip Technology (SELDI TOF MS), the maternal plasma of 53 chromosomally-normal control and 28 Down's syndrome affected pregnancies was profiled between 10 and 20 weeks' gestation. Preliminary studies demonstrated two distinct phases of changes in protein expression, the first at 10-14 weeks and second at 14-20 weeks. Using this data, analysis of the 10-14 weeks' plasma samples (Down's syndrome n=13, control n=20) showed the presence of a protein of mass 100.3 kDa that was elevated in the Down's syndrome group compared to the controls (p<0.002). This protein was further isolated using SAX Q-spin columns and identified using QTOF MS and Western blotting as being plasma protease C1-inhibitor. Analysis of the 14-20 week cohort demonstrated changes in protein expression of three additional proteins. Two of these proteins were found to be up-regulated (serum amyloid P-component, p<0.004 and transthyretin, p<0.006) and complement C3-α chain was observed to be down-regulated (p<0.0005). The identification of these biomarkers in maternal plasma and their potential to improve current Down's syndrome screening are discussed., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Conventional whole-body MRI at 1.5 T does not provide adequate image quality of small fetuses, thus reducing its potential for use as an alternative to invasive autopsy. High-field whole-body MRI at 9.4 T provides good images of small animals. We therefore compared the diagnostic usefulness of high-field MRI with conventional MRI for post-mortem examination of human fetuses., Methods: We did whole-body MRI at 9.4 T and 1.5 T on 18 fetuses of less than 22 weeks' gestation, using three-dimensional T(2)-weighted fast-spin echo sequences, before doing invasive autopsy. Images obtained with MRI for each system were compared with the findings of invasive autopsy in a blinded manner. Tissue contrast of 14 different regions was compared on 1.5 T and 9.4 T images that were provided by paediatric radiologists separately and in a random order, and image quality was scored on a four-point scale. The primary endpoint was diagnostic accuracy., Findings: Spatial resolution, tissue contrast, and image quality of all organ systems were much better with high-field MRI than with conventional MRI. All structural abnormalities that were detected with invasive autopsy and internal examination of visceral organs were also detected with high-field MRI, whereas conventional MRI was not diagnostically useful in 14 (78%) cases., Interpretation: Whole-body high-field MRI is a feasible option for post-mortem examination of human fetuses, and can provide good tissue characterisation even in small fetuses (5 g). The use of MRI at 9.4 T might be helpful in the development of a minimally invasive perinatal autopsy system., Funding: Department of Health Policy Research Programme, British Heart Foundation, National Institute of Health Research, Higher Education Funding Council for England, Biotechnology and Biological Sciences Research Council, Engineering and Physical Sciences Research Council, Great Ormond Street Hospital, University College London (UCL) Institute of Child Health, UCL Hospital, and UCL.

Dysplastic kidneys are common malformations affecting up to 1 in 1000 of the general population. They are part of the spectrum of Congenital Abnormalities of the Kidney and Urinary Tract (CAKUT) and an increasing number of children are being diagnosed on antenatal ultrasound. In the past, these patients may not have been detected until adulthood following investigation for other illness, or even as incidental findings at post mortem, unless there was severe bilateral dysplasia leading to Potter's sequence or renal failure in childhood. Excluding syndromic cases with defects in other organ systems, features linked to worse prognosis at presentation are: (1) bilateral disease; (2) decreased functional renal mass (which encompasses not just small kidneys but also large ones where cysts replace normal architecture); (3) lower urinary tract obstruction; and (4) anhydramnios or severe oligohydramnios. Dysplasia and renal function are dynamic and can evolve during pregnancy, so repeated assessment is necessary when pathology is expected. Worsening dimensions or decreasing amniotic fluid levels imply poorer prognosis, but there are no proven therapies during pregnancy, though vesicoamniotic shunting may be indicated with obstruction. Postnatal investigations aim to define the anatomy, which helps to estimate risks of infection and kidney function. Management might then involve observation, prophylactic antibiotics, surgery and/or renal support. Risks of renal malignancy and hypertension are low during childhood, but longer-term follow-up is needed, particularly to determine blood pressure and renal function in adulthood and pregnancy. Around 10% of cases have a family history of significant renal/urinary tract malformation. Monogenic causes include mutations in individual genes, such as TCF2/hepatocyte nuclear factor 1ss (HNF1beta), PAX2 and uroplakins, but there are also recent reports of children with compound heterozygote mutations in several renal/urinary tract developmental genes. Effective genetic screening in future may require gene chip or other techniques to assess multiple genes concurrently, but this should not replace a multidisciplinary approach to these often difficult cases.

Prenatal fetal sex determination is undertaken in women at high risk of serious genetic disorders affecting a specific sex. Traditionally, this is undertaken by invasive testing, usually chorionic villus sampling, which carries a risk of miscarriage of around 1%. The identification of cell-free fetal DNA in the maternal circulation has allowed the development of 'non-invasive prenatal diagnostic tests', which permit fetal sex determination without risk to the pregnancy.

RhD blood group incompatibility between a pregnant woman and her fetus can result in maternal alloimmunization and consequent haemolytic disease of the newborn (HDN) in subsequent pregnancies. The D-negative blood group is found in 15% of whites, 3-5% of black Africans, and is rare in Asians. Recent technological advances in non-invasive prenatal determination of the fetal RHD status using cell-free fetal DNA (cffDNA) have opened new avenues for the management of D-negative pregnant women. In this review applications for the high risk women, as well as potential for routine screening will be discussed. The use of non-invasive prenatal diagnosis and the management of other blood incompatibilities will also be discussed.