Fetal anomalies affect up to 3% of pregnancies and are diagnosed by prenatal ultrasound scans. As standard of care in these cases, fetal samples are usually taken by amniocentesis or chorionic villus sampling. Genetic testing is routinely performed on these samples employing techniques such as karyotyping, quantitative fluorescent PCR or chromosomal microarray analysis. These methods will mainly detect deletions or duplications/insertions with a diagnostic resolution of no more than 10,000 bp. In cases where families have previously been affected by known genetic disorders targeted testing for specific genes or micro-deletions can also be requested.

The current standard testing methods are detecting genetic variation less than half the time. A next generation sequencing approach allows the determination of the exact genomic sequence, significantly increasing the resolution of the analysis down to single nucleotide variations.

This is expected to increase the diagnostic yield and to enable the discovery of novel genetic disorders impacting on fetal development. Future implementation of new routine prenatal diagnostic sequencing promises to improve genetics‐derived prognoses and allow more informed parental counselling as well as management of pregnancy and childbirth.

Prior to the adoption of any new diagnostic testing, studies must demonstrate clinical and analytical validity of the sample analysis. The PAGE study represents the first larger, UK-wide study for the assessment of exome and whole-genome sequencing for prenatal analysis of congenital abnormalities.

PAGE logistics

The PAGE study is collecting sample trios, each consisting of samples from the baby, mum and dad. A total of 1000 sample trios will be analysed by exome sequencing and about 20 will also be analysed by whole-genome sequencing.

The samples will be taken at local NHS Fetal Medicine Units and will undergo testing with the currently established routine diagnostic assays as standard of care. Only those samples in which no trisomy is detected will be entered into the PAGE analysis pathway (see figure). NHS Diagnostic Laboratories in Birmingham (WMRGL at the Birmingham Women's Hospital, BWH) and London (NETRGL at Great Ormond Street Hospital, GOSH) will anonymise all samples before providing the purified DNA to the Wellcome Sanger Institute in Cambridge which is a renowned centre for high-throughput sequence analysis.

Bespoke bioinformatics tools will be used to apply clinical filtering to highlight variants likely to cause the fetal anomalies. These data will be thoroughly reviewed by a panel of experienced clinicians to ensure clinical validity before reports are provided back to the NHS Diagnostic Laboratories. The NHS Diagnostic Laboratories will validate each result before linking it back to the patient and providing a report to the local genetics teams who will feed the results back to the families.

Anonymised data on possible genetic causes of the babies' problems will be shared internationally through databases such as DECIPHER and the complete anonymised datasets will be shared with biomedical researchers through the European Genome-phenome Archive (EGA) to allow controlled access for researchers investigating genetic conditions of early development that manifest during pregnancy.

Significant results from this study will be published in peer-reviewed journals but no data will be presented that will allow individuals to be identified. The research is organised by the Wellcome Sanger Institute and is funded through the Health Innovation Challenge Fund, awarded by the Wellcome Trust and the Department of Health.

PAGE Logistics: the flow of samples and data.

PAGE Logistics: the flow of samples and data.

Social Science

In addition to the basic science work that is being performed as part of the PAGE project we will also be undertaking social science work using qualitative methods. This means we will be talking to women and their partners when they have consented to be part of the PAGE project to find out what they think and feel about this potential new prenatal test.

We will ask to speak to women after they have first accepted testing and we will follow some of these women up to talk to them again a year later. Women will also be asked if they would like to take part if they have had a result from the PAGE project showing that there was a genetic reason found for the difference seen on ultrasound.

The conversation will be recorded and then transcribed and anonymised. We will then analyse the data using qualitative methods so we can start to understand what women feel and think about the test and what particular issues they have with the testing. This enables us to discover aspects of the testing and ethical concerns that researchers cannot necessarily anticipate. This part of the project will be lead by the University of Birmingham.

The results from the qualitative work will be used to inform future best practice guidelines in this area.

The PAGE Ethics Research Programme

The development of genomic approaches to prenatal testing being developed by the PAGE project offers the potential for a better understanding of prenatal structural anomalies in the fetus and ultimately for improved patient care and more informed reproductive decision making. In addition to the scientific and clinical challenges of achieving this, the introduction of new reproductive technologies also presents a number of ethical issues. The successful and appropriate development and introduction into clinical practice of technologies such as prenatal genomics requires these problems to be identified, understood and carefully analysed in the development of models of good ethical practice.

In recognition of the importance of considering ethical factors at an early stage, the PAGE project has established an ethics programme to be carried out by Professor Michael Parker and Dr Ruth Horn of the Ethox Centre at the University of Oxford. Working closely with the PAGE scientific team, and the social science research group at Birmingham University, the PAGE ethics programme will provide ethics support and advice to the PAGE partners and will carry out a programme of ethics research likely to include the following:

  • a critical review of the existing literature and relevant professional guidelines followed by the publication of a discussion paper;
  • a national expert working party bringing together relevant stakeholders including patient groups, fetal medicine centres, cytogenetic teams (DNA preparation and validation laboratories), clinical geneticists, the teams within the Sanger Institute, and other relevant health professionals to map out the key practical issues likely to arise and important relevant (potentially conflicting) principles;
  • drawing on the literature review, working party and experience of providing ethics support to PAGE, conduct a case-based ethical analysis of the issues to inform the development, with relevant stakeholders, of draft principles of good practice including the identification of problematic areas of practice where tensions are likely to arise between important professional and ethical commitments;
  • a national ‘consensus conference’ bringing together some of the same key stakeholders who attended the working party together with policy-makers to discuss and agree a shared position on key principles of good practice for the effective and appropriate translation of genomic approaches to prenatal screening into the NHS;

The Ethox Centre is an internationally-recognised multidisciplinary bioethics research centre located within the Nuffield Department of Population Health at the University of Oxford. Ethox aims to improve ethical standards in healthcare practice and in medical research through education, research, and the provision of ethics support to health professionals and medical researchers. The Centre aims in all its activities to be close to practice and seeks to engage with ethical issues faced by real world actors in real world settings. An implication of this is that particular value is placed on approaches to research bringing together empirical social science research and ethical analysis. The Centre’s research activities focus on four areas: global health ethics; clinical ethics; research ethics; and population health ethics.

For more information about the PAGE Ethics Research Programme please contact Professor Michael Parker or Dr Ruth Horn.


  • Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities.

    Drury S, Williams H, Trump N, Boustred C, GOSGene, Lench N, Scott RH and Chitty LS

    Prenatal diagnosis 2015;35;10;1010-7

  • Prenatal exome sequencing for fetuses with structural abnormalities: the next step.

    Hillman SC, Willams D, Carss KJ, McMullan DJ, Hurles ME and Kilby MD

    Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology 2014;45;1;4-9

  • Exome Sequencing in Fetuses with Structural Malformations.

    Mackie FL, Carss KJ, Hillman SC, Hurles ME and Kilby MD

    Journal of clinical medicine 2014;3;3;747-62

  • Evaluation of non-invasive prenatal testing (NIPT) for aneuploidy in an NHS setting: a reliable accurate prenatal non-invasive diagnosis (RAPID) protocol.

    Hill M, Wright D, Daley R, Lewis C, McKay F, Mason S, Lench N, Howarth A, Boustred C, Lo K, Plagnol V, Spencer K, Fisher J, Kroese M, Morris S and Chitty LS

    BMC pregnancy and childbirth 2014;14;229

  • Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound.

    Carss KJ, Hillman SC, Parthiban V, McMullan DJ, Maher ER, Kilby MD and Hurles ME

    Human molecular genetics 2014;23;12;3269-77

Data Access

Accessing PAGE data

Responsible sharing of data from families participating in the PAGE study is crucial to maximising our understanding of genetic conditions of early development that manifest during pregnancy, while protecting privacy and confidentiality. Therefore, anonymised PAGE study data will be shared with research and clinical communities as follows:

Likely diagnostic variants

Variants in genes that are likely to cause or contribute to the observed fetal anomaly will be linked to anonymised records in the DECIPHER web portal hosted by the Wellcome Sanger Institute and will become publicly accessible with associated clinical information, such as the nature of the fetal anomaly, once the clinical team has had sufficient time to inform the family.

For over 10 years, clinicians and researchers from around the world have used the DECIPHER web portal to improve their interpretation of genetic variants observed in their patients. Through DECIPHER, clinicians and researchers can contact the PAGE team to discuss potential follow-on research.

Genomic datasets

All genomic data from exome and genome sequencing (BAM files and VCF files) and clinical data files will be available through the European Genome-phenome Archive hosted by the European Bioinformatics Institute (EBI).

These anonymised data will only be made available to researchers investigating genetic conditions of early development that manifest during pregnancy who commit to protecting the confidentiality and privacy of research participants. Researchers requesting access to these anonymised data must apply by completing a data access form detailing their particular research aims; access will only be granted after approval by the PAGE data access committee.

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