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Objective: In the West Midlands regional genetics service, cases of perinatal death with a possible genetic diagnosis are evaluated by the perinatal pathology genetic multidisciplinary team (MDT). The MDT assesses autopsy findings and suggests appropriate genomic assessment. The objective of this retrospective service evaluation was to determine the clinical utility of the MDT in assessing perinatal deaths associated with structural anomaly. This is the first evaluation since the introduction of whole‐genome and whole‐exome sequencing in routine clinical care. Methods: This was a retrospective service evaluation including all cases of perinatal death with an associated structural anomaly and suspected genetic etiology that underwent perinatal MDT assessment between January and December 2021. All cases received a full or partial postmortem examination and at least a chromosomal microarray analysis. Demographic characteristics, phenotype, genotype, MDT recommendations, diagnoses, outcomes and impact of postmortem analysis and genetic testing data were collected from patient case notes. Results: Overall, 123 cases were discussed at the MDT meetings in 2021. Genetic evaluation was recommended in 84 cases and accepted in 64 cases. A range of genetic tests were requested according to indication and availability. Thirty diagnoses were made in 29 cases from 26 unrelated families. The diagnostic yield was 24% (29/123) in all cases or 45% (29/64) in cases with a suspected genetic diagnosis who underwent genetic testing. Postmortem examination provided clinically actionable phenotypic data in 79% of cases. A genetic diagnosis enabled accurate recurrence risk counseling and provision of appropriate follow‐up, including prenatal testing and preimplantation diagnosis for patients with inherited conditions. Conclusions: Genomic testing was a clinically useful addition to (but not a substitute for) postmortem examination in cases of perinatal death associated with structural anomaly. The MDT approach helped assess cases and plan appropriate follow‐up. Expedited whole‐genome sequencing or panel‐agnostic analysis were most appropriate for heterogeneous presentations. This broad approach can also expand knowledge of prenatal phenotypes and detect novel disease genes, and should be a priority in future research. © 2024 International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

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. Key points: What is already known? Congenital heart abnormalities are the most commonly occurring congenital anomalies and can be associated with chromosomal or monogenic conditions.With the increasing use of fetal sequencing, there is a need to define the association between monogenic conditions and specific cardiac abnormalities, particularly when isolated to facilitate triaging for prenatal sequencing. What does this study add? The incremental yield of prenatal exome sequencing over and above chromosome microarray for congenital heart abnormalities is 9.3% in isolated lesions and 35.2% in the presence of complex lesions/heterotaxy.Clinicians should consider the clinical utility of offering prenatal exome sequencing in selected isolated cardiac lesions dependent on resources available. [ABSTRACT FROM AUTHOR]

The article explores the limitations of systematic reviews and meta-analyses in evaluating the clinical usefulness of genomic investigations in prenatal diagnosis. It discusses issues such as publication bias, limited phenotyping, and variations in statistical analyses. The article also addresses challenges specific to cell-free DNA screening, including bias in combining rare anomalies and follow-up bias. While acknowledging the importance of these studies, the authors stress the need to consider their limitations when interpreting results. The article suggests alternative approaches to determine the diagnostic yield of genomic tests and emphasizes the significance of optimal study design and reporting. [Extracted from the article]

This article, titled "The incremental yield of prenatal exome sequencing over chromosome microarray for congenital heart defects: a systematic review and meta-analysis," aims to determine the additional diagnostic value of prenatal exome sequencing (pES) compared to standard testing for fetuses with congenital heart defects (CHD). The study reviewed the literature from January 2010 to February 2023 and identified 1957 cases. The results showed that pES provided an increased diagnostic yield for all CHD, isolated CHD, and CHD associated with extracardiac malformations (ECMs) of 17.4%, 9.3%, and 35.9% respectively. The most common anomalies in fetuses with ECMs were gastrointestinal, central nervous system, and neck/skin anomalies. The study also identified the most common genetic syndrome and mode of inheritance. The authors concluded that the likelihood of a monogenic cause for CHD with extracardiac anomalies is high, but clinicians should consider the clinical utility of offering pES in selected cases. [Extracted from the article]

Answering climate change challenges, the paper proposes an intelligent decision support system (DSS) for the management of green-blue infrastructure (GBI). Addressing the gaps identified in other studies, the designed DSS incorporates four key elements: 1/interdisciplinary collaboration among all stakeholders 2/inclusion of practical operation and maintenance activities, 3/main components of distributed DSS, with practical examples of use, 4/consideration of conditions specific to the location. The multi-layered DSS architecture can be implemented as a unified platform that provides a comprehensive, customizable, and flexible framework based on AI tools, big data and analytics, edge computing, cloud, and mobile, IIoT, and biometric system tools. The use of cobots and digital clones alongside humans results in the implementation of hybrid human-machine units. DSS for GBI increases decision-making capacity and can serve as a foundation for the implementation of similar systems by governments and local communities to build sustainable and resilient communities. [ABSTRACT FROM AUTHOR]

Objectives: First, to determine the uptake of prenatal exome sequencing (pES) and the diagnostic yield of pathogenic (causative) variants in a UK tertiary fetal medicine unit following the introduction of the NHS England Rapid Exome Sequencing Service for fetal anomalies testing (R21 pathway). Second, to identify how the decision to proceed with pES and identification of a causative variant affect perinatal outcomes, specifically late termination of pregnancy (TOP) at or beyond 22 weeks' gestation. Methods: This was a retrospective cohort study of anomalous fetuses referred to the Liverpool Women's Hospital Fetal Medicine Unit between 1 March 2021 and 28 February 2022. pES was performed as part of the R21 pathway. Trio exome sequencing was performed using an Illumina next‐generation sequencing platform assessing coding and splice regions of a panel of 974 prenatally relevant genes and 231 expert reviewed genes. Data on demographics, phenotype, pES result and perinatal outcome were extracted and compared. Descriptive statistics and the χ‐square or Fisher's exact test were performed using IBM SPSS version 28.0.1.0. Results: In total, 72 cases were identified and two‐thirds of eligible women (n = 48) consented to trio pES. pES was not feasible in one case owing to a low DNA yield and, therefore, was performed in 47 cases. In one‐third of cases (n = 24), pES was not proposed or agreed. In 58.3% (14/24) of these cases, this was because invasive testing was declined and, in 41.7% (10/24) of cases, women opted for testing and underwent chromosomal microarray analysis only. The diagnostic yield of pES was 23.4% (11/47). There was no overall difference in the proportion of women who decided to have late TOP in the group in which pES was agreed compared with the group in which pES was not proposed or agreed (25.0% (12/48) vs 25.0% (6/24); P = 1.0). However, the decision to have late TOP was significantly more frequent when a causative variant was detected compared with when pES was uninformative (63.6% (7/11) vs 13.9% (5/36); P < 0.0009). The median turnaround time for results was longer in cases in which a causative variant was identified than in those in which pES was uninformative (22 days (interquartile range (IQR), 19–34) days vs 14 days (IQR, 10–15 days); P < 0.0001). Conclusions: This study demonstrates the potential impact of identification of a causative variant by pES on decision to have late TOP. As the R21 pathway continues to evolve, we urge clinicians and policymakers to consider introducing earlier screening for anomalies, developing robust guidance for late TOP and ensuring optimized support for couples. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

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 determine the incremental yield of antenatal exome sequencing (ES) over chromosomal microarray analysis (CMA) or conventional karyotyping in prenatally diagnosed congenital heart disease (CHD). Methods: A prospective cohort study of 197 trios undergoing ES following CMA or karyotyping owing to CHD identified prenatally and a systematic review of the literature were performed. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov (January 2000 to October 2019) databases were searched electronically for studies reporting on the diagnostic yield of ES in prenatally diagnosed CHD. Selected studies included those with more than three cases, with initiation of testing based upon prenatal phenotype only and that included cases in which CMA or karyotyping was negative. The incremental diagnostic yield of ES was assessed in: (1) all cases of CHD; (2) isolated CHD; (3) CHD associated with extracardiac anomaly (ECA); and (4) CHD according to phenotypic subgroup. Results: In our cohort, ES had an additional diagnostic yield in all CHD, isolated CHD and CHD associated with ECA of 12.7% (25/197), 11.5% (14/122) and 14.7% (11/75), respectively (P = 0.81). The corresponding pooled incremental yields from 18 studies (encompassing 636 CHD cases) included in the systematic review were 21% (95% CI, 15–27%), 11% (95% CI, 7–15%) and 37% (95% CI, 18–56%), respectively. The results did not differ significantly when subanalysis was limited to studies including more than 20 cases, except for CHD associated with ECA, in which the incremental yield was greater (49% (95% CI, 17–80%)). In cases of CHD associated with ECA in the primary analysis, the most common extracardiac anomalies associated with a pathogenic variant were those affecting the genitourinary system (23/52 (44.2%)). The greatest incremental yield was in cardiac shunt lesions (41% (95% CI, 19–63%)), followed by right‐sided lesions (26% (95% CI, 9–43%)). In the majority (68/96 (70.8%)) of instances, pathogenic variants occurred de novo and in autosomal dominant (monoallelic) disease genes. The most common (19/96 (19.8%)) monogenic syndrome identified was Kabuki syndrome. Conclusions: There is an apparent incremental yield of prenatal ES in CHD. While the greatest yield is in CHD associated with ECA, consideration could also be given to performing ES in the presence of an isolated cardiac abnormality. A policy of routine application of ES would require the adoption of robust bioinformatic, clinical and ethical pathways. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]