Genomics is now firmly embedded into clinical care within the NHS and many people are interested to know what it is all about.

This FAQ sheet is for your general information only and is not part of the consent process for any diagnostic test or research project.

What are “genetics” and “genomics”?

Genetics is the science of genes, the units of code inside every cell in our bodies that provide the instructions for making the building blocks or proteins. We know a lot about how genes are made and how they are passed on from parents to children. We understand how some genes affect how we develop and grow. Sometimes changes occur in a gene which may cause the protein it makes to be affected and this can be the cause heritable diseases, including some types of immunodeficiency. Genes are made of DNA. In between the genes themselves there is a lot of DNA that we don’t understand very well. Some of this DNA may actually control how and when the genes are turned on and off, so we need to study this as well. Genomics is the study of the whole of our DNA (the “genome”) and how variations in its sequence affect us in health and disease.

What is genomic medicine?

Although human genomes are all 99.9% identical, the fraction that is different, or varies, can have a major influence on our lives and health. Genomic medicine seeks to look at and describe those differences (“variants”). We are each born with our own genetic make up and we all have genetic variation which is what makes us unique. Most variation is not relevant to our health, but some genes are so important that a single change in the genetic code might be enough to affect a whole arm of the immune system. This is called an inborn error of immunity and more than 450 of them have been discovered so far.

Other, so-called “polygenic” traits might be influenced by the additive effects of many variations across several genes or nearby regions of DNA. Over our lifetimes, we also accumulate new changes in our DNA – sometimes these change the way our cells behave, and might contribute to cancer. We are still learning about all these different types of genomic variation.

What is whole genome sequencing?

The first human genome was sequenced through an enormous international effort and took more than 10 years to complete. But with widespread new technology, whole genomes can now be sequenced in a matter of days or weeks, in time to inform the care of patients with inherited diseases. Usually a blood sample is a good starting point for extraction of DNA which is a very long molecule. The DNA is broken up into short segments for sequencing and these short segments or reads are then matched to a benchmark “reference” sequence. The resulting composite genome sequence (represented as a string of letters) is stored securely and confidentially on a large computer server. It can be compared to other people’s genomes to identify similarities and differences, some of which might be linked to illness. Whilst the testing itself is quick, this process of comparing and analysing the data can take time and some genetic testing in the NHS can take around a year to report results. Often it is useful during the testing to compare with the DNA of other members of the family to see if a gene change has arisen for the first time in that individual or has been inherited, which may have health implications for other family members.

In the NHS, whole genome sequencing is now the method of choice for the diagnosis of suspected inborn errors of immunity. This is because it reliably reports the sequence of all the genes known to be linked to such disorders and also some of the sequence in between, which may affect how the genes work. In fact, when your doctor requests testing for inborn errors of immunity, only this subset of immune genes will be analysed for variation, not the whole genome.

Sometimes with whole genome testing a variant is identified and it may be easy to interpret its importance for disease, for example if the same variant has been described in other people with the same illness and not in healthy individuals. In this case your medical team will be able to report back the cause of the immunodeficiency, which may have an impact on your medical treatment and/or may provide information which is of relevance to your current or future family. Often, though, there is some uncertainty around the significance of rare variants – specifically it is important to determine if a variant is thought to be causing disease or is a part of normal variation, such a result is called a “variant of uncertain significance” or “VUS”. To try to understand the variant further there might be a need for further testing, which may include offers of research testing, or if possible testing other family members.

Will whole genome sequencing give a definite cause for my PID?

Not necessarily. Many patients do not obtain a genetic diagnosis from whole genome sequencing. Some of them may not have a single-gene cause for their illness at all. In other cases, diagnostic information may be present within the whole genome sequencing data without its significance being recognised at the time of testing because of incomplete scientific knowledge. Scientists and doctors may be able learn more about your unique variants and how they link to your illness through research. This is why, when discussing whether to have whole genome sequencing as a diagnostic test in the NHS, you may at the time or subsequently be invited to consent to research analysis of your DNA sequence. Additionally your NHS team may be able to review your stored whole genome data in the future as more genes that can cause PID will be identified over time. Either way, by consenting to research you will be contributing to helping others and not just yourself.

What happens if an abnormality unconnected to my immunodeficiency is found?

This is an important question. Many people carry variants that are known to cause disease or make a disease more likely to occur. Examples include genes associated with cancers or other conditions that don’t occur till later in life. Sometimes people carry a genetic change which is not causing a problem for them, but might affect other family members including children who have inherited the same variant. This is one of the reasons why the initial NHS whole genome testing only looks specifically at genes already linked to the type of disease a person has, in your case immunodeficiency; however even then, genes can have more than one job and unexpected results may be found. Your doctor will talk to you about this when you consent to testing both in the NHS and if applicable on a research basis. You may also wish to talk to a genetic doctor and/or counsellor about the issues of an unexpected finding, or the implications of any genetic variants found on your current or future health, or that of your family; you can ask your doctor for a referral to genetic medicine services.

How long will research on my whole genome sequence take?

That is a hard question to answer. In the NHS on average the testing is taking around a year and this is to look at the genes that we currently know cause PID. However, genomics research is at an early stage and there is a lot to learn. When possible new genetic disorders are discovered then many further experiments are still needed to work out whether it is likely to be causing the immune problem. If other individuals with the same condition are found to have the same sorts of variants, then that could also increase confidence that this is a cause of the condition. Scientists need to be sure of such a link before feeding back to your doctor about a new diagnosis – it is important not to give wrong information. That is why reporting of this sort of result may take many years.

Where can I find more information about genomic medicine and related research?