The Aim of the Study

The aim of this study is to develop better ways of detecting genetic causes of structural anomalies observed on ultrasound scan within pregnancy. To do this we will use next generation sequencing technology, a new 'molecular' laboratory method, which allows us to pick up very small changes in the baby's genes. Our genes act as instructions for passing on inherited characteristics such as eye colour and height from parent to child. Sometimes changes in our genes cause certain diseases or conditions. To find out more about genes and the genome, please follow this link: What is a genome?

In order to diagnose certain chromosomal problems in pregnancy, a procedure known as amniocentesis (a sample taken from the fluid surrounding the baby) or chorionic villus sampling (CVS) (a sample taken from the placenta) is needed.

We are developing new molecular methods that look at a baby's genes in much more detail when women have a CVS or amniocentesis. We would like to find out if the molecular methods give us as much or more information than the current methods do. In this study we will not be able to give any results from the new laboratory method within the pregnancy. We hope to be able to do this for future parents.

Before we can offer any new tests routinely it is important to ensure they work well and are accurate. To do this we need the help of parents with complicated pregnancies to collect samples that will allow us to compare these new tests with those in current use.

Apart from exploring the technical aspects of these new tests, the study will also look at any ethical questions relating to the new tests and the personal experience of the patients during the study.

Participation in PAGE

We know that the particular appearance on your baby's ultrasound scan may be associated with changes in your baby's chromosomes or genes. Therefore you will have been offered an amniocentesis or CVS to test for certain genetic changes such as trisomies (extra copy of an entire chromosome).

You can participate in the PAGE study if the testing of your amniocentesis or CVS sample did not detect any trisomies and if the ultrasound scan showed a nuchal translucency (fluid at the back of the baby's neck) of larger than 4 mm, or one or more structural anomalies at any time in pregnancy after 11 weeks gestation. Your partner (the father of your baby) should also consent to the PAGE study; both of you must be at least 16 years of age and you should both be able to understand the study patient information provided by your clinical team.

We know that it can be a distressing time for you when a scan shows that your baby is not developing as expected. We are grateful to you for thinking about participating in the PAGE Study.

What will happen to me if I take part?

If you agree to take part we will ask you and your partner to donate an additional blood or saliva sample (blood sample is preferable). We are not asking permission to take any extra CVS or amniocentesis samples, we will use DNA left over after the standard clinical tests have been performed.

These new tests are very sensitive and may also detect minor changes that won't affect the health of your baby. These changes can be inherited from either parent. For this reason we need to test you and your partner's DNA at the same time as testing your baby's DNA so that we know which changes are new in your baby, and so might be important, and which are inherited from you or your partner. We also seek permission to ask your doctor, or check your hospital notes to confirm the outcome of the pregnancy and the results of any tests done. With your agreement we may contact you when your baby is around 2 years old to arrange a follow-up to find out how he/she is developing.

These new tests are still in development and the results of this research will not be available during the course of your pregnancy. If we find any information that explains your baby's problems, we will inform your doctor who will contact you. This research study is designed to improve the diagnosis of unexpected problems in the developing baby, so we will not seek or feed back any findings not related to your pregnancy.

In some cases you may be asked if you would like to share your thoughts about your genetic testing experience with fetal medicine specialists. Your views as a parent will be very valuable, helping us to shape clinical services and tests in the future. See also: Social Science section.

What happens to the samples in the PAGE study?

1. CVS, Amniocentesis or fetal blood samples are collected and in addition blood samples are taken from both parents.

2. At the NHS diagnostic laboratories the samples will be anonymised and DNA is purified from all samples.

3. DNA arrives at Sanger Institute. After an initial quality control, analysis will look for genetic causes of the observed fetal anomalies (exome and whole-genome sequencing).

4. Results fed back to families by local clinical genetics service.

5. Results from consenting families deposited in secure databases for further research.


We will follow ethical and legal practice and all your information will be handled in confidence. Any information you give us will only be used in the course of the research to develop these new tests. Any samples and data stored will be stored securely.

They will be coded, and no personal data (for example name and address) will be available to the researchers. In the event that we identify specific gene changes that might explain your baby's condition we will deposit these changes and the anonymised information in large international databases containing similar information to allow us to identify babies anywhere else with similar problems and a similar change in their genes.

This helps us understand which gene changes might explain your baby's problems and which are more likely to be minor changes that are unlikely to affect health.

To advance research and maximise our understanding of the effect of any gene changes on the health of babies, all the anonymised data will be shared with other medical researchers in a secure manner, but only if these researchers commit to keep these anonymised data secure.

Researchers can request access to anonymised information on variants likely to explain the structural anomalies (via the DECIPHER database) or the anonymised genomic dataset containing all genetic information (via the European Genome-phenome Archive, EGA). Publications of anonymised study results in scientific journals will also be a way of communicating new findings to a wider research and clinical community, paving the way for further progress in diagnosing and understanding of genetic conditions causing developmental problems during pregnancy.

What is a genome

Video resource: Zoom in on your genome - female

Every cell in your body has a complete set of instructions about how to make your cells and their components, and to direct how these interact. This set of instructions is your genome. Your genome is quite similar to everyone else's genome, which is why we all turn out to be human beings. You could think of your genome as a recipe book that carries all of the instructions to make a human being.

What are genomes made of?

The human genome consists of 46 chromosomes.

The human genome consists of 46 chromosomes.

Your genome is made of a chemical called deoxyribonucleic acid or DNA. All living organisms have DNA packaged into their cells. In animals DNA is tightly packaged into bundles, wrapped around a scaffold of protein. If we look at DNA under a microscope, we can sometimes see these bundles of protein and DNA, called chromosomes.

The amount of DNA and the number of chromosomes in an organism's cells depends on the species it comes from. Humans have 46 chromosomes, actually 23 pairs of chromosomes, one chromosome of each pair coming from the mother and the other chromosome from the father. If you are thinking about the genome as a recipe book you could see the chromosomes as chapters in the book.

DNA's alphabet

Video resource: From DNA to protein - 3D

DNA's code is written in only four 'letters', called A, C, G and T. The meaning of this code lies in the sequence of the letters A, C, G and T in the same way that the meaning of a word lays in the sequence of alphabet letters. Your cells read the DNA sequence one recipe at a time, each contained within a functional region of DNA, called a gene. These genes usually code for a protein. In our cells, proteins are the workforce; they get everything done. Proteins break down our food to release energy. Proteins organise the transport of useful chemicals between cells. Often, these useful chemicals are themselves proteins.

As well as doing things, proteins are the building blocks for most of your body. In the same way that a wall is made mostly of bricks, your body is made mostly of protein.

Less than 2% of the genome codes for protein. The rest of the DNA is made up of the same letters as coding DNA but it doesn't have the same meaning. We are not sure what all of this non-coding DNA is for. We know that some of it controls when genes are switched on or off and others are important for the structure of chromosomes. However we are still finding out what much of this DNA does.

What is a mutation?

Between generations or over a lifetime genomes change. These changes are called mutations. Mutations are happening in your cells all the time. They can happen spontaneously and at random. You can also inherit from your parents mutations that arose many generations ago. This is why diseases can run in families.

If a mutation happens in a part of the DNA that does not code for a protein or regulate when a gene is switched on or off, the chances are that the mutation will have no health consequences for the individual. However, some mutations can be detected because they alter the structure of a protein or the amount of protein produced. These relatively few mutations can directly affect the ability of the protein to carry out its normal job.

However, some mutations can be detected because they lead to a change in the coding parts of a gene and result in a change to the protein structure or amount of protein produced. These relatively few mutations directly affect the ability of the protein to carry out its job or change the way the protein does its job.

Different types of mutation

Mutations come in many different shapes and sizes: a single letter may be changed, a whole segment of DNA sequence may be flipped over and reverse itself, or huge sections of the genome could be duplicated or deleted. A few of these changes can be seen under a high-powered microscope but most require techniques (such as Microarray or Exome sequencing) that can compare the sequence or activity of specific DNA segments.

Single letter changes are also called point mutations.

Single letter changes:

This is where a single letter in the DNA sequence is changed. This is equivalent to a spelling error in a word of our genome recipe book. This is detectable by exome sequencing.


An additional copy of chromosome 21 causes Down' syndrome.

Copy number:

Small or large sections of DNA can be duplicated or deleted in different individuals. These duplications or deletions can have a dramatic effect on the health of an individual. For example people with Down's syndrome have an additional copy of chromosome 21 causing a condition with significant physical differences and learning difficulties. This is equivalent to a word, paragraph or even a whole chapter of our genome recipe book being repeated or deleted; an additional copy of a chromosome is called a trisomy. This is detectable by microarray or when the repetition or deletion is larger by standard karyotyping.



Small or large sections of DNA can be can be reversed (an inversion) or swapped between different chromosomes (a translocation). For example, some forms of the blood disorder haemophilia are caused by short segments of the Factor VIII gene being inverted or reversed inside the gene. This is equivalent to a paragraph or pages of our genome recipe book being removed and pasted back in the wrong way (an inversion) or removed and pasted in a different chapter (a translocation). This is detectable by standard karyotyping.

DNA and genetic disorders

Mutations in DNA and their implications in human diseases have been known about for many years. However, recent studies looking at the entire genome are rapidly increasing our understanding of the different types of genetic variant that cause genetic conditions.

Although most of the time these forms of mutation have no visible impact on an individual's health, in some people they have been found to be the cause of birth defects or genetic disorders.

DNA sequencing technology

The technology we will be using in the PAGE study is called sequencing. This involves reading the exact order of letters - As, Cs, Gs and Ts - along a piece of DNA. This is the most detailed genetic test possible. It allows us to read the entire genome 'recipe book' from start to end, or to dip in and out and read selected chapters of particular importance.

Using sequencing, we are able to detect extra or missing words and spelling mistakes. This technology means that we should be able to find any changes to the DNA that might have caused structural anomalies in prenatal ultrasound screening. However, interpreting this information is very complicated as there is no appropriate reference to turn to, like a dictionary.

Every individual has a unique DNA sequence and there are lots of tiny genetic differences between all of us, some common and some rare. This makes finding the genetic differences which cause a particular disorder much more challenging.

One of the ways that we can start to make sense of whether the changes are important and are causing problems or not is to record results anonymously in an international database. This way clinicians and scientists around the world can start to build up a picture of what are the likely important differences in DNA and start to form this 'DNA dictionary'.

Useful Links

  • Antenatal Results and Choices is a charity for parents wanting information and support on all aspects of antenatal screening. The charity is member of the PAGE consortium; their website provides a wealth of information and many useful links.
  • Healthtalk Online: Personal experiences of antenatal screening, including decision-making after a prenatal diagnosis.
  • Contact a Family: Information, support and advice for families with a child with any disability or special need, including expectant parents with a prenatal diagnosis. Information about a wide range of conditions, including rare conditions.
  • Unique is a UK-based charity that provides information and support to families and individuals affected by any rare genetic disorder.
  • Syndromes Without A Name is a project run by Genetic Alliance UK offering support and information to families of children with undiagnosed conditions.
  • Genetic Alliance UK is the national charity of patient organisations supporting all those affected by genetic disorders.
  • Genetic and Rare Disorders Organisation is a non governmental organisation based in Ireland acting as a national alliance for voluntary groups representing the views and concerns of people affected by or at risk of developing genetic or other rare disorders.
  • Wellcome Sanger Institute is a charitably funded genomic research institute which focuses on understanding the role of genetics in health and disease.
  • is a website intended to help people understand genetics and genomic science plus the implications for us all.
  • is a website on the latest developments in the fast-moving world of human genomics.
  • Genomics England is a flagship project set up by the Department of Health to deliver 100,000 whole genomes from NHS patients by 2017. Initially the focus will be on rare disease, cancer and infectious disease.
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