Impact case study database

Invasive testing, amniocentesis or chorionic villus sampling, is offered to women where the fetus is at risk of a genetic disorder. These tests usually involve inserting a needle into the womb and carry a small risk of miscarriage, causing psychological stress to women. Further, fetal anomalies occur in around 2% of all pregnancies and many arise from genetic disorders. The inability to diagnose the underlying cause in fetuses with ultrasound abnormalities results in parental anxiety and difficulties in decision making. Research at UCL, to develop non-invasive genetic tests and rapid prenatal genome sequencing, is transforming patient care by reducing the psychological stress associated with these high-risk pregnancies, offering safer diagnosis to high-risk families and improving the diagnosis of genetic conditions in fetuses with abnormalities. Consequently, since 2013, more than 1,950 pregnant women in England have avoided invasive testing and more are now benefiting from timely prenatal genetic diagnosis that is informing pregnancy management and decision-making. These tests are now included in the National Genomic Test Directory in England’s new Genomic Medicine Service, enabling access for all women who could benefit from these tests.

Increasing patient access to safer, non-invasive prenatal tests

GOSH, with UCL’s GOS ICH, was the first centre in the world to deliver an accredited NIPD service for monogenic conditions. Since 2013, the UCL team has extended the availability of safer prenatal tests for conditions where the pregnancy is at risk of a monogenic disorder, including many very rare conditions and definitive diagnosis for recessive conditions, even when parents carry the same mutation. In 2018 there were approximately 840,000 conceptions in England and Wales and approximately 640,000 live births (ONS figures). The tests developed at UCL, are now available through the NHS, to every at-risk woman in England ( S1).

This earlier, safer analysis of maternal plasma to identify fetuses with these abnormal genes is more acceptable to parents who seek testing, as it removes the anxiety and risk of miscarriage, associated with invasive testing ( S2). Since 2013, in the UK, more than 1,950 women at risk for >160 conditions have benefited from these non-invasive tests. A third of all prenatal molecular diagnostic tests offered by GOSH are now non-invasive ( S3).

The tests are increasing uptake of prenatal diagnosis; approximately 40% of parents said they would undergo invasive prenatal testing for CF, whereas 94% said they would opt for NIPD, including those who had previously declined invasive testing ( S4). The GOS ICH team receives requests for testing from as far afield as Canada and Australia.

Implementation of the prenatal diagnostic tests developed at UCL is allowing parents to receive appropriate care, sooner. The director of Antenatal Results and Choices (ARC) said, “For parents who carry single gene disorders, every pregnancy is fraught as they face testing to find out whether their baby has inherited the condition. We have supported many such parents and for them the possibility of having NIPD early in their pregnancy rather than undergo invasive testing is of huge benefit. The work you [Professor Chitty] have done to make this a reality for a number of conditions makes a real difference to the parent experience. We know that, for some, availability of such testing actually influences their decision to embark on a pregnancy“( S5).

The UCL team has also created a repository of plasma samples collected from parents with pregnancies at risk of chromosomal defects (aneuploidy) or genetic conditions (RAPID biobank). Since 2013, RAPID has almost doubled in size and now includes over 20,000 parental blood samples. This provides a valuable resource for service development at GOSH, across the UK, and for quality assurance schemes. The National Laboratory and Scientific Lead (Genomics Unit) for NHS England & NHS Improvement said, “The UK National External Quality Assessment Service (UK NEQAS) for Molecular Genetics runs an external quality assurance scheme for laboratories worldwide for fetal sexing, common aneuploidies and most recently common microdeletions. The RAPID biobank was instrumental in supporting the development, and now annual delivery of this international programme and has thus played a key role in ensuring the quality of cell free fetal DNA testing globally.” ( S6).

Providing rapid diagnostic testing through rapid fetal exome sequencing

Having an accurate diagnosis during pregnancy supports decision making and facilitates improved clinical management. Difficult decisions about continuing or terminating a pregnancy can be made with more certainty and inform pregnancy and early neonatal management to improve long-term outcomes.

One healthcare professional said, “In the last 12 months, you and your team have provided timely diagnostic information in several complex prenatal cases which has been truly transformational. We can only hope that this standard of care can become standard practice, nationally and internationally in not-too-distant future”. Another clinician said, “Being able to offer couples genomic testing to help make a diagnosis empowers them to take a decision about their pregnancy with much clearer information than from scans alone”. Prospective parents who had been given the results of tests felt that testing made “a very difficult decision much easier as they knew the prognosis for the baby would be very poor. Having this information for the decision helped them emotionally deal with it and with their recovery. They were extremely grateful for the service.” ( S7).

Rapid fetal exome sequencing was launched in 2020 as an accredited service at GOSH and is increasing the number of families receiving an accurate diagnosis for the abnormality identified in their unborn child. The team’s research has also influenced national guidance for this new service. Approximately 2200 families a year can now access the service, with better information, pregnancy management and improved outcomes ( S8).

Raising public awareness of non-invasive prenatal diagnosis and the importance of genome sequencing

The UCL team engaged the public through the media, publications and discussion groups to gauge parental and societal opinion. Chitty regularly delivers lectures to lay society annual meetings for organisations such as Antenatal Results and Choices (ARC) and the Brittle Bones Society. The team has developed an animation for young people describing whole genome sequencing that was evaluated with 554 school pupils (11-15 years) and shown to increase objective knowledge scores. Interviews with 12 young people and 14 parents offered genome sequencing found positive views and feelings of empowerment to take an active role in decision making ( S9). These animations are widely available on public websites including Genomics England ( S10) and have been translated into Turkish, Chinese and Bengali. The animation has received almost 30,000 views on YouTube and when uploaded on Sina Weibo (Chinese Twitter), it received a further 136,800 views in one week.

NHS implementation

Chitty has advised NHS England Rare Disease Working Group on the implementation of these tests and through extensive engagement with patients, the public, health professionals and commissioners this multidisciplinary research programme has led to inclusion of the tests in the new NHS National Genomic Test Directory ( S1). The NHS now funds NIPD and rapid fetal sequencing as part of the new national Genomic Medicine Service, making the tests available to all women across England.