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Implementation and clinical utility of transcriptome sequencing by RNA-seq in EB (Uitto 2)

Project lead Dr Jouni Uitto
Organisation Thomas Jefferson University, Jefferson Medical College, Philadelphia, USA
Project budget USD 195,754.00
Start date / Duration 01. Dec 2016 / 24 months
Funder(s) / Co-Funder(s) DEBRA Austria, MSAP/EBEP Recommended
Research area EB genetics, epigenetics & biology

Project details

Short lay summary

EB is a group of genetic diseases where mutations in different genes result in blistering and fragility of the skin and mucous membranes. Identification of the mutated genes and the specific type of mutations in each individual patient is critical for proper subclassification of the disease, and it is helpful for predicting the severity of the disease early on during childhood. Knowledge of the specific mutation is also required for the application of some new therapies that are currently being developed for the treatment of patients with specific types of mutations. Thus, knowledge of the individual’s mutation is critical for the application of appropriate therapies.

The strategies used for mutation detection at this point are only partially (80%) effective, and many of the patients do not know their specific mutations. Furthermore, the knowledge of certain types of mutations is suggestive but does not confirm, of the consequences of the mutations. In this study, we propose a new strategy, which will increase the yield of mutations and their specific consequences.

The patients participating in this study may be asked to give a small skin biopsy (~3-4 mm in diameter). This biopsy, which is done under local anaesthesia, carries a small risk of pain and infection which, however, can be treated by pain killers and appropriate antibiotic therapy.

Identification of specific types of mutations in a gene is the prerequisite for the development of new treatments of precision medicine for EB. The currently proposed work, which will identify specific mutations in affected individuals, is a prerequisite for applying the actual treatments to an individual patient. It is unclear at this point as to how long it will take before such treatments will be available to the patients.

The risks of identifying the mutations, as proposed in this study, are minimal and relate to the skin biopsy (see above).

We estimate that 50 patients with different forms of EB will be enrolled in the study. All patients with an established diagnosis of EB are potentially eligible for the study.

Scientific summary

In this project, we have adopted a new technique, so-called RNA-seq, which utilizes next-generation sequencing of RNA, and not DNA as in the traditional systems. It is expected that this RNA-seq technique will significantly increase the yield of mutations in families with EB, and it will also provide critical insight to the pathomechanistic details leading from mutations to clinical presentation. We have now applied this RNA-seq technique to different forms of EB, and our preliminary results have shown intriguing findings which may, to a certain extent, explain the variability noted in different affected individuals with EB, even if their mutations are in the same gene and in some cases are precisely the same. Our plan is to extend these observations to additional cases with EB, and eventually develop guidelines that explain the correlations between the clinical severity and underlying mutations.

Strategic relevance

Epidermolysis bullosa is a group of heritable diseases, and there are as many as 20 different genes that are now known to harbor mutations resulting in skin fragility and blistering. The knowledge of specific mutations in each affected individual and the family is important for confirmation of the diagnosis, subclassification, and prognostication of the disease severity. The techniques used up to this point, based on DNA sequencing, identify only about 80% of the mutations in patients with EB, and often the consequences of the mutations are not entirely clear.

As there is currently no specific or effective treatment for EB, any of the ongoing developments of precision medicine approaches based on the knowledge specific types of mutations would be an advance to the subgroup of patients with such a specific mutation.


What did this project achieve?

The project's approach allowed the resolution of VUS (variants of unknown significance) and enabled the consequences of mutations at the RNA level that escape genomic recognition. The team has tried to obtain RNA from cheek swabs, but this approach did not worked.


RNA seq
Thomas Jefferson University
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