Ill without diagnosis: the reality of Variants of Unknown Significance

Children suspected of having a metabolic disorder can wait years in uncertainty for a diagnosis. For some of these children, the diagnosis never comes. Despite extensive genetic research, no cause for their symptoms is found. During her PhD, Irena Muffels developed a way to better and more quickly help these children. She defended her thesis on September 25.

Ill, but a lack of diagnosis

Being seriously ill without a clear cause, diagnosis, or possible treatment: for approximately 60 children in the Wilhemina Children’s Hospital, this is a daily reality. These children show a wide range of symptoms that point towards metabolic disease. The cause of which, however, cannot be found, despite extensive genetic research.

Metabolic diseases are the result of genetic abnormalities that prevent cells from functioning properly. The cells may produce too little energy, waste products are not broken down (sufficiently), or not enough building blocks are being produced. This wide range of potential consequences complicates finding a suitable treatment when the cause is unknown, Irena explains: ‘Often, we can only treat symptoms. Children with motor delays get physical therapy, and for problems with speech development, they get speech therapy. Diets are also commonly applied. The approach is usually a matter of trial and error. Unfortunately, often little can be done for these children without a diagnosis, as the cause of their complaints is unknown.’

Genetic error, or simply variation?

A known genetic error is found for 20-25% of children with suspected metabolic disorders, leading to a diagnosis. For the others, only genetic ‘Variants of Unknown Significance’ are found, Irena explains: ‘Everyone has variations in their DNA, but these are usually benign. Changes in the genetic code are also found in children with metabolic diseases, but the meaning of those changes is often unknown. Is the genetic variation pathogenic and the cause of their symptoms, or is it simply benign diversity?’

The result of this complex puzzle is a long wait for patients to receive their diagnosis, or in some cases no diagnosis at all. The long waiting time, the result of research into the genetic variation through experiments in a specialised laboratory, brings with it uncertainty. Irena: ‘Parents do not know what to expect. They know that something is wrong, and that it is likely to be a genetic disorder, but that confirmation is lacking. They do not know what will happen to their child, because they cannot compare them to other children with the same disease. That is a difficult situation for everyone involved.’

Scanning cells for faster diagnoses

During her PhD, Irena investigated how these children can be helped more quickly: ‘Metabolic diseases can cause problems in different places in the cell, making it difficult to know where to focus your experiments. To make that easier, we have developed a type of MRI scan, in which we search for metabolic abnormalities in the patient’s skin cells. The approach was designed as a funnel: we checked the cells for their metabolic functionality in multiple domains. If our test showed that the functionality was disrupted in one of those domains, we searched more specifically for the underlying error within that domain.’

The results were positive, explains Irena: ‘This approach worked very well in patients with a “wrong” gene of which the function was already somewhat known. For patients with a genetic variation of which we did not know the function, the scan appeared to be promising, but the test still needs further development.’

Testing treatments on patient cells

In addition to a faster diagnosis, Irena’s method had another important application: ‘The scan provides insight into how the cells behave. Ultimately, we were able to use the scan to test new treatments. As we use the patient’s own cells, the response of these cells to the treatment is a good predictor of the body’s response. When the cells functioned better after the treatment, we also applied the treatment to the patients.’

Moving forward, but the challenge remains

Despite this new approach, finding the right treatments for these patients remains a major challenge. Irena: ‘Detecting the errors is difficult itself, but even if we know where the error is, treatments are usually not available. No treatment has yet been developed for most metabolic diseases, and they are one of the leading causes of death among children in the Netherlands.’

Nevertheless, Irena is positive about the future: ‘We are getting better and better at detecting these errors and finding their meaning. Being able to test treatments on the patient’s cells is also a major step forward. In addition, genetic therapies are being developed and may eventually become effective treatments for all children who receive a diagnosis.’

The next step: continuing as a doctor

Continuing this line of research, Irena is currently working in New York as a postdoctoral researcher, developing treatments for children with genetic disorders: ‘We grow “mini-brains” from the patients’ cells in order to be able to test new treatments on them.’ After this, Irena wants to continue as a clinical geneticist to work on better treatments for genetic disorders.