Evidence to Support the Clinical Utility of Prenatal Exome Sequencing in the Evaluation of the Fetus with Congenital Anomalies (Scientific Impact Paper No. 64)
This Scientific Impact Paper examines past and more recent evidence on the use of prenatal exome sequencing and outlines what this test adds to current practice in identifying congenital anomalies. The clinical and technical considerations are identified, and importantly the ethical implications and challenges are acknowledged.
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This Scientific Impact Paper was developed prior to the emergence of the COVID-19 coronavirus. Please note that the information provided in this paper will be considered for update 3 years after publication, with an intermediate assessment of the need to update 2 years after publication.
This is the first edition of this paper.
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.
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.
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, sometimes results are difficult to interpret and genetic changes can be found where their significance for the pregnancy is unclear.
This paper reviews some of the latest studies, along with earlier evidence on ES and provides clinicians with guidance for future practice.
Declaration of interests (guideline developers)
Dr F Mone MRCOG, Birmingham: None declared.
Dr DJ McMullan, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust: None declared.
Dr D Williams, West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust: None declared.
Professor LS Chitty MRCOG, London: PAGE study applicant and received research funding from the Health Innovation Challenge Fund (HICF); received funding from EU Horizon 2020 and the National Institute for Health Research Biomedical Research Centre to develop rapid fetal exome sequencing.
Professor ER Maher, Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Department of Medical Genetics, University of Cambridge and Cambridge Biomedical Research Centre, National Institute for Health Research: PAGE study applicant and received research funding from the Health Innovation Challenge Fund (HICF). Received honorarium and expenses from Illumina for meeting attendance.
Professor MD Kilby FRCOG, Birmingham: Chief investigator for the PAGE study funded by the Wellcome Trust and the UK Government Department of Health and Social Care. Fetal Medicine Lead for the West Midlands, Oxfordshire and Wessex Genomics Laboratory Hub. Member of the Fetal Genomics Group of the British Society of Genetic Medicine and representative on the Genetics and Genomics Joint Committee of Royal Colleges. Member of the RCOG Genomics Taskforce. Received research funding from the Health Innovation Challenge Fund (HICF).