Why is genetic testing necessary?

DNA is the building block of life that leads to formation of protein, cells, tissues, organs; that make up a healthy functioning body. We inherit our DNA from our parents, that is packed in genes. Sometimes errors in the DNA can lead to a genetic disorder. EB is one such genetic disorder, that is caused by an error in genes leading to disrupted protein expression that is manifested by skin fragility, mucous membrane, and mechanically induced injuries. EB can present in variable severities and thus categorized in four main types, accordingly.
In EBS, the splitting and blistering of skin occurs within the upper layer, epidermis, in JEB, the basement membrane, between the epidermis and underlying dermis is involved. In DEB, basement membrane between within the superficial dermis is involved. In KS, the blistering occurs at different levels and multiple layers within the skin.

Splitting of skin can occur at different levels, and that is determined by the involved gene that carries the fault.  There are over 20 genes, indicated to cause EB, spanning across the severity spectrum. These genes carry information for proteins that are present in the skin, which include collagens, laminin’s and integrins. The errors in the genes encoding these proteins lead to the clinical presentation of EB where the skin loses its resistance and integrity.
Therefore, a genetic test or a laboratory diagnosis becomes essential to determine the (sub)type of EB and the precise cause of the disease at the genetic (DNA) and protein level.

Genetic Testing is necessary for

  • Prediction of disease severity and prognosis.
  • Ensuring appropriate global patient care enabling patient recruitment in possible clinical trials.
  •  Offering accurate genetic counselling and risk assessment for future pregnancies.
  • Enabling informed reproductive decision-making for couples who are carriers. 
  • Offering options of preimplantation or prenatal genetic diagnosis in next pregnancy.

What are the methods of genetic testing?

There are two main methods used in EB laboratory diagnosis: Genetic testing aims to identify the specific disease-causing sequence variant(s) on DNA obtained from a blood sample. Skin sample analysis using techniques that work on the protein level looks at changes in protein expression, localisation, and ultrastructural modifications (changes in skin components that can only be seen by electron microscopy).

Why is it essential to get our child tested?

An early and reliable genetic diagnosis can make a significant difference to the family. A confirmed diagnosis can provide information for the family to understand the real impact on their life and care requirements looking into the future. It can guide health professionals to appropriate treatment, pain management, and wound care. In severe cases, it can also help ensure the family makes the most of their time with their newborn with appropriate psychological support. Access to genetic testing is essential in EB suspected cases in the first few weeks of life.

Genetic Counselling

In newborns, a skin sample analysis should be the first diagnostic step because it delivers rapid results. At the same time, genetic testing should always be performed. In cases with typical clinical features, genetic testing by different techniques, in particular, Sanger sequencing (SS) or next-generation sequencing (NGS), can deliver a final diagnosis.
In EB (sub)types with an expected complex genetic background, or in cases with uncharacteristic clinical features, or an unclear cause, genetic testing by NGS is recommended.
If a disease-causing variant (or variants) is detected by genetic testing in a person with EB, their parents should be tested to determine the pattern of inheritance. Other family members can be tested to allow genetic counselling.

Results from a genetic test:

  • A positive impact means that a disease-causing variant (or variants) has been identified and explains EB’s cause.
  •  An unclear result means that a “new” (previously unknown) variant (or variants) has been identified, and the consequence of this variant is unknown.
  • A negative result means that no disease-causing variant (or variants) has been identified in EB- associated genes.

Available Options for Diagnosis

Any laboratory that undertakes EB diagnosis is therefore recommended to consider the testing criteria formulated and agreed by the “Clinical practice guidelines” However, there are vast variations and differences among EB clinical and diagnostic centers worldwide concerning the diagnostic equipment and methods available and between the national health system regulations governing rare disease care and genetic testing and reimbursement for these services. Therefore, it may be difficult that all the criteria set out in the publication above are met. Such situations may require EB clinicians and diagnostic scientists to make a reasonable adjustment, provided that such adjustment does not deviate significantly from the guideline.