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Determining the molecular basis of currently uncharacterised forms of Epidermolysis Bullosa (McGrath 18)

Project lead Professor John McGrath
Organisation Guy's and St Thomas NHS Foundation Trust, London, UK
Project budget GBP 87,792.00
Start date / Duration 01. Nov 2011 / 29 months
Funder(s) / Co-Funder(s) DEBRA UK, EB MSAP/EBEP Recommended
Research area Molecular therapy

Project details

Short lay summary

An exciting, powerful new tool that improves our ability to read the order of or “sequence” human genes is now being employed in research in EB, opening up significant possibilities of increased understanding of the underlying genetics of the condition. This will improve diagnosis and, in the long-term, contribute to research that is looking for a treatment for EB. In addition, genetic information is invaluable in counselling couples at risk of having children with EB and allowing prenatal testing in high-risk situations.

Many diseases are caused by abnormal behaviour of a gene – it is said to have ‘mutated’ or changed. Identifying the gene(s) associated with a disease provides a launch-pad for improved diagnosis and developing better, more effective treatments. EB presents quite a challenge, since it is a complex condition occurring in different forms; to date18 different genes and over 1,000 different mutations have been identified as being involved.

An important step when someone is first thought to have EB is an accurate and rapid diagnosis; genetic profiling makes this possible. But while the profile of some families with EB has been established, for many individuals/families the genes involved remain a mystery and no diagnosis is possible. This new technique, called ‘whole exome sequencing’ (WES), will - it is hoped - allow the genetic problem in these people to be revealed (all of our genes together are called the genome; the exome is a very small part of the genome, but carries most of the mutations important in certain disease conditions).

This study aimed to use WES to look at 20 families with unclassified forms of EB to try and discover the relevant gene(s) and mutation(s) involved. The first results have been published in a prestigious medical journal (British Journal of Dermatology) in summer 2014.

Strategic relevance

Previously, genes were identified by taking a skin biopsy and blood sample, followed by several complex laboratory investigations which did not always give a clear-cut answer. This current study showed that WES can identify mutations more simply, cheaply and accurately using just the blood sample. So previously undiagnosed patients can be classified and appropriate treatment can be rapidly instigated; doctors also have important information for genetic counselling. The added bonus was that a new form of EB was identified, extending our knowledge of the condition.

Understanding what is happening in the genes provides a foundation on which knowledge, understanding and improved diagnosis can be built and assist those scientists looking for treatments for EB.

“Making quick and accurate diagnoses is very important for people with EB. This information is vital in improving genetic counselling and in planning optimal healthcare and future treatments. Our challenge is to take the research data and introduce the findings into everyday clinical practice. We want next generation sequencing to become an everyday tool when diagnosing EB.” Professor John McGrath.

What did this project achieve?

One of the most important steps when someone is first thought to have EB is to make an accurate and quick diagnosis. Usually this involves sampling a piece of skin and examining this under the microscope and then sequencing DNA from a blood sample. This approach works in most cases of EB, but sometimes it doesn’t and no diagnosis is possible. This study looked at a new technique of screening DNA called whole-exome sequencing (WES). This method sequences all 21,000 genes at the same time and then filters the results to find the faulty gene. The reaserach team found that WES can increase the number of genetic abnormalities we find in EB compared to established techniques. In addition, because WES is not limited to known EB genes it also allows us to look for new genes – and indeed the researchers found one in this study. This gene (called EXPH5) causes a new form of EB simplex which is now included in the latest (2014) international consensus classification of EB. The team would now like to introduce WES into more routine diagnostic work for EB. It will take another 1-2 years to improve the speed of the technique but the longer term hope is that they will be able to diagnose EB using WES without having to rely on skin sampling so much. One other possible advantage of WES is that because it sequences all the genes, the data it generates may help them to improve the predictions of how someone with EB will fare in the future.

More on DEBRA UK's website.


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