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ObjectivesTo 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.MethodsA 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.ResultsOverall, 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%).ConclusionThe 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.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% i

This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non, Dondorp, Wybo de Wert, Guido Bombard, Yvonne Bianchi, Diana W Bergmann, Carsten Borry, Pascal Chitty, Lyn S Fellmann, Florence Forzano, Francesca Hall, Alison Henneman, Lidewij Howard, Heidi C Lucassen, Anneke Ormond, Kelly Peterlin, Borut Radojkovic, Dragica Rogowski, Wolf Soller, Maria Tibben, Aad Tranebjaerg, Lisbeth van El, Carla G Cornel, Martina C eng RP-PG-0707-10107/Department of Health/United Kingdom Research Support, Non-U.S. Gov't England 2015/03/19 06:00 Eur J Hum Genet. 2015 Nov;23(11):1438-50. doi: 10.1038/ejhg.2015.57. Epub 2015 Mar 18.

Dondorp, Wybo de Wert, Guido Bombard, Yvonne Bianchi, Diana W Bergmann, Carsten Borry, Pascal Chitty, Lyn S Fellmann, Florence Forzano, Francesca Hall, Alison Henneman, Lidewij Howard, Heidi C Lucassen, Anneke Ormond, Kelly Peterlin, Borut Radojkovic, Dragica Rogowski, Wolf Soller, Maria Tibben, Aad Tranebjaerg, Lisbeth van El, Carla G Cornel, Martina C eng Published Erratum England 2015/10/16 06:00 Eur J Hum Genet. 2015 Nov;23(11):1592. doi: 10.1038/ejhg.2015.109.

Dondorp, Wybo de Wert, Guido Bombard, Yvonne Bianchi, Diana W Bergmann, Carsten Borry, Pascal Chitty, Lyn S Fellmann, Florence Forzano, Francesca Hall, Alison Henneman, Lidewij Howard, Heidi C Lucassen, Anneke Ormond, Kelly Peterlin, Borut Radojkovic, Dragica Rogowski, Wolf Soller, Maria Tibben, Aad Tranebjaerg, Lisbeth van El, Carla G Cornel, Martina C eng RP-PG-0707-10107/Department of Health/United Kingdom England 2015/04/02 06:00 Eur J Hum Genet. 2015 Apr 1. pii: ejhg201556. doi: 10.1038/ejhg.2015.56.

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.