A cheaper, faster method for sequencing EB genes could mean earlier diagnosis, giving families greater understanding of disease impact and access to appropriate support.

 

Dr Ene-Choo Tan works at a hospital in Singapore where 12-15 people with EB symptoms, after consenting to genetic testing, will give a small blood sample. This project will sequence genes known to be involved in EB using different methods to identify and improve the best way to quickly get accurate results. 

Read more in our researcher's blog.

 

Contents:

• Project summary (top of page)
• About our funding
• Latest progress summary
• About our researchers
• Why this research is important
• Researcher's abstract
• Researcher's progress update

 

About our funding:

Research leader	Dr Ene-Choo Tan
Institution	KK Women's & Children's Hospital, Singapore
Type of EB	All types of EB
Patient involvement	12-15 people to be genetically tested for EB
Funding amount	£10,500
Project length	1 year
Start date	1 March 2024
DEBRA internal ID	GR000044

 

Latest progress summary:

Due 2025.

 

About our researchers:

Lead researcher: Dr Tan is trained as a molecular geneticist, with a Master of Science degree from the University of Wisconsin – Madison and PhD from the Institute of Molecular and Cell Biology. 

Co-researcher: Dr Koh is a paediatric dermatologist with special interest in genetic skin disorders, including EB. He helped to set up DEBRA Singapore and frequently collaborates with other paediatric dermatologists from around the region to manage patients with EB.

 

Why this research is important:

Although some cases can be diagnosed clinically, the overlapping and age-related presentations makes it challenging to make an accurate diagnosis of the specific type. Getting a genetic diagnosis in EB will enable the accurate diagnosis of the specific subtype, which is important for long-term prognosis and appropriate management of symptoms.… The identification of genetic mutation is also important for prenatal testing in severe cases and familial testing of biological relatives, and guides decisions on family planning.

Dr Tan

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Researcher’s abstract:

Grant title: Improving the genetic diagnosis of epidermolysis bullosa by long-read sequencing.

Epidermolysis bullosa (EB) is a rare condition characteriszed by skin fragility, leading to blisters and erosions on minor trauma. In certain types of EB, scarring can occur secondary to the blisters and erosions. Apart from the skin, EB can also affect mucosal surfaces lined by epithelium, such as the mouth, oesophagus, gastrointestinal tract, urinary tract, and eyes. Scarring in these tissues can occur, leading to further complications such as strictures. EB can also lead to other complications such as anaemia, poor growth, and orthopaedic issues, as well as an increased risk for certain types of skin cancers, such as squamous cell carcinoma. All four main types of EB (EB simplex, junctional EB, dystrophic EB, and Kindler syndrome) are caused by genetic abnormalities. As EB is clinically heterogeneous with a spectrum of severity and overlapping presentations, it can be difficult to distinguish between the main types, as well as the more than 30 clinical subtypes, especially during the early years of life. Molecular confirmation should be done for definitive diagnosis to help in predicting long-term outcome and guide appropriate treatment. Success rate in obtaining a positive result through genetic testing ranges from 50–90% for the current methods of single-gene Sanger or multi-gene short-read sequencing. Long-read sequencing has not been used extensively to investigate multiple EB genes. The Nanopore long-read technology can sequence long fragments of DNA to allow more complete sequencing of the whole gene can result in better yield in uncovering underlying genetic mutations, providing a more accurate diagnosis.

The clinical features of the various types of EB can overlap and often pose a diagnostic dilemma in early life. Early and accurate genetic testing can lead to prompt diagnosis of the EB subtype, providing better prognostication and improved management as well as to anticipate and monitor for complications. Currently, genetic testing is by simultaneous sequencing of multiple genes or the exome (gene-containing regions of the genome), which typically sequences short fragments. Nanopore sequencing of longer fragments (including non-coding regions) can potentially result in higher diagnostic yield and uncover more genetic variants. Getting a positive genetic result is important for patients. In severe paediatric cases, it is important to have closure for parents and aid in future pregnancy. Identifying the genetic variant in a proband also allows the assessment of risk for the extended family. Information on the genetic defect can also be used for carrier testing for recessive forms of EB where the two defective alleles are inherited from both parents who each carry a defective copy. Genetic testing can also be performed to identify spontaneous mutations for dominant forms of EB for prenatal or pre-implantation testing. To better understand the clinical disease course underlying EB symptoms, we would need more genetic variants to be identified in multiple patients to better correlate the genetic data with disease presentations. Uncovering more genetic variants would also lead to better understanding of the molecular processes during disease pathogenesis, which may lead to the development of new pharmacological agents and other treatments.

 

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Researcher’s progress update:

Due 2025.

 

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Image credit: National Human Genome Research Institute (NHGRI).