Genotype-phenotype correlation in junctional epidermolysis bullosa
Research type
Research Study
Full title
Genotype-phenotype correlation in junctional epidermolysis bullosa
IRAS ID
290183
Contact name
Adrian Heagerty
Contact email
Sponsor organisation
University Hospitals Birmingham NHS Foundation Trust
Clinicaltrials.gov Identifier
NCT04727268, Clinicaltrials.gov reference number
Duration of Study in the UK
0 years, 5 months, 20 days
Research summary
Summary of Research
Junctional epidermolysis bullosa (JEB) is a rare genetic skin disease where genetic defects in skin proteins result in extensive blistering in response to mild mechanical stress. Patients are often affected at birth or from early childhood, and suffer from varying degrees of severity depending on the specific mutations that they have and the proteins that are affected. This ranges from severe widespread blistering and death within the first few years of life (severe JEB), to minimal localised blistering and survival to adulthood (intermediate JEB). Diagnosis is confirmed by genetic testing, and this is often used to predict the likely clinical course. However, it is not always straightforward to accurately make predictions from genetic information, as our understanding of these proteins and mutations at the molecular level is currently incomplete.
The main aim of this project is to systematically collect genetic and clinical data of junctional epidermolysis bullosa (JEB) patients and to explore whether there are any relationships between participants’ genetic defects and the severity of disease. This will help in establishing links between genetic defects and clinical characteristics, which is essential for accurate prognostication, genetic counselling and prenatal diagnosis.
This study will also aim to develop pipelines for analysis of how mutations may affect corresponding protein structure and function using computer prediction tools. This will improve our understanding of how these proteins function, and could partly explain the variation in disease severity of patients with this condition. It could also lead to identification of important regions of the protein, which could be investigated further in subsequent studies.
Summary of Results
This study was sponsored by University Hospitals Birmingham NHS Foundation Trust and received funding from the Dystrophic Epidermolysis Research Association (DeBRA-UK). The study took place across two hospitals (Solihull Hospital and Birmingham Children’s Hospital). It explored the relationship between participants’ genetic defects and the severity of their disease in individuals with junctional epidermolysis bullosa (JEB).
JEB is a rare genetic skin disease where genetic defects in skin proteins (mutations) result in extensive blistering of the skin and other organs in response to mild mechanical stress. Patients are often affected at birth or from early childhood, and suffer from varying degrees of severity depending on the specific mutations that they have and the proteins that are affected. This ranges from severe widespread blistering and sometimes death within the first few years of life (severe JEB), to minimal localised blistering and survival to adulthood (intermediate JEB). Diagnosis is confirmed by genetic testing, and this is often used to predict the likely clinical course.
Investigators in the study collated and reviewed data that was routinely available in participants’ records. This included the mutations present and the severity of disease. Seventeen participants with JEB were included in the study. Seven participants had severe JEB, nine had intermediate JEB and one had laryngo-onycho-cutaneous (LOC) syndrome. Twenty-one mutations from four different genes were identified in these individuals, and seven of the mutations have not been reported before. The mutations identified had different effects on how DNA was interpreted by the cell. Some mutations affected DNA processing and further analysis by computer programs provided some predictions which could potentially explain why disease was mild, intermediate or severe.
This study has improved our understanding of how genetic defects in JEB result in disease. It highlights that looking at how DNA is processed, in addition to the mutation itself, is important in predicting how severe disease will be. It also emphasises the need for a centralised database of mutations associated with JEB and the corresponding clinical features of these individuals.
REC name
London - London Bridge Research Ethics Committee
REC reference
21/PR/0911
Date of REC Opinion
23 Jul 2021
REC opinion
Further Information Favourable Opinion