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

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.