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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]

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]

The discovery of cell-free fetal DNA (cffDNA) in maternal plasma has enabled a paradigm shift in prenatal testing, allowing for safer, earlier detection of genetic conditions of the fetus. Non-invasive prenatal testing (NIPT) for fetal aneuploidies has provided an alternative, highly efficient approach to first-trimester aneuploidy screening, and since its inception has been rapidly adopted worldwide. Due to the genome-wide nature of some NIPT protocols, the commercial sector has widened the scope of cell-free DNA (cfDNA) screening to include sex chromosome aneuploidies, rare autosomal trisomies and sub-microscopic copy-number variants. These developments may be marketed as 'expanded NIPT' or 'NIPT Plus' and bring with them a plethora of ethical and practical considerations. Concurrently, cfDNA tests for single-gene disorders, termed non-invasive prenatal diagnosis (NIPD), have been developed for an increasing array of conditions but are less widely available. Despite the fact that all these tests utilise the same biomarker, cfDNA, there is considerable variation in key parameters such as sensitivity, specificity and positive predictive value depending on what the test is for. The distinction between diagnostics and screening has become blurred, and there is a clear need for the education of physicians and patients regarding the technical capabilities and limitations of these different forms of testing. Furthermore, there is a requirement for consistent guidelines that apply across health sectors, both public and commercial, to ensure that tests are validated and robust and that careful and appropriate pre-test and post-test counselling is provided by professionals who understand the tests offered. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether less invasive methods of autopsy would be acceptable to bereaved parents and likely to increase uptake.Design: Mixed methods study.Setting: Bereaved parents recruited prospectively across seven hospitals in England and retrospectively through four parent support organisations.Sample: Eight hundred and fifty-nine surveys and 20 interviews with bereaved parents.Methods: Cross-sectional survey and qualitative semi-structured telephone interviews.Main Outcome Measures: Likely uptake, preferences, factors impacting decision-making, views on different autopsy methods.Results: Overall, 90.5% of participants indicated that they would consent to some form of less invasive autopsy [either minimally invasive autopsy (MIA), non-invasive autopsy (NIA) or both]; 53.8% would consent to standard autopsy, 74.3% to MIA and 77.3% to NIA. Regarding parental preferences, 45.5% preferred MIA, 30.8% preferred NIA and 14.3% preferred standard autopsy. Participants who indicated they would decline standard autopsy but would consent to a less invasive option were significantly more likely to have a lower educational level (odds ratio 0.49; 95% CI 0.35-0.70; P = 0.000062). Qualitative findings suggest that parents value NIA because of the lack of any incision and MIA is considered a good compromise as it enables tissue sampling while easing the parental burden associated with consenting to standard autopsy.Conclusion: Less invasive methods of autopsy are acceptable alternatives for bereaved parents, and if offered, are likely to increase uptake and improve parental experience. Further health economic, validation and implementation studies are now required to assess the viability of offering these in routine widespread clinical care.Tweetable Abstract: Mixed methods UK study finds less invasive methods of autopsy are acceptable alternatives for bereaved parents, and if offered, are likely to increase uptake and improve parental experience. [ABSTRACT FROM AUTHOR]

Background: Postmortem examination is the single most useful investigation in providing information to parents about why their baby or child died. Despite this, uptake remains well below the recommended 75%.Objective: To address the question 'what are the barriers and motivators to perinatal, prenatal and paediatric PM examination?'Search Strategy: Key databases including Pubmed and CINAHL; Cochrane library, websites of relevant patient organisations, hand search of key journals, first and last authors and references.Selection Criteria: Peer-reviewed qualitative, quantitative or mixed methods research examining factors affecting uptake or decline of perinatal or paediatric postmortem examination.Data Collection and Analysis: Narrative synthesis; findings were compared across studies to examine interrelations.Main Results: Seven major themes describing barriers to postmortem uptake were identified: dislike of invasiveness, practicalities of the procedure, organ retention issues, protective parenting, communication and understanding, religion and culture and professional or organisational barriers. Six major themes related to factors which facilitated parental consent were identified: desire for information, contributing to research, coping and well-being, respectful care, minimally invasive options, and policy and practice. There were a number of themes in the literature that reflected best practice.Conclusion: Findings highlight the need for better health professional education and the fact some concerns may be mitigated if less invasive methods of postmortem were routinely available. New consent packages and codes of practice may have a positive impact on perception of examination after death. The landscape is changing; further research is necessary to assess the impact on postmortem uptake rates.Tweetable Abstract: Systematic review to explore the barriers and motivators to perinatal, prenatal and paediatric postmortem examination. [ABSTRACT FROM AUTHOR]