"Many people think it is crazy that we are still finding new diseases"

You are head of a research group in clinical genetics. What does your research focus on?

"We focus on diseases in which heredity probably plays a role. In the last four years that I have been leading my own research group, we have discovered about five new syndromes. People sometimes find it strange that we are still discovering new diseases in the year 2022. Yet this is not so strange because today's technology makes much more possible. In the last ten years, we have become much better at looking at the genome, but that is still only 2% of our hereditary material. It is at the interface with the unknown part, that is, the other 98 percent, that our research is focused.

Until a few years ago, the remainder was regarded as junk DNA because it had no function. It has now become clear that the control of our genes is done by that 98 per cent. You could say that they are the switches that turn the lights on or off. If a lamp doesn't work, the lamp itself may be broken, but it could also be the switch or the wiring. Gaining more insight into how our genes are controlled is one of the main lines of our research. We hope to find new forms of heredity of diseases."

What can you do with these insights?

"By discovering new syndromes, you can offer clarity to patients who currently cannot get a genetic diagnosis. If you have been walking around with unexplained symptoms for a long time, a diagnosis can really provide an answer. In this way, you can spare patients years of tests and scans, and that saves on healthcare costs in the long run. If there is a question of heredity, you can also make statements about the risk of recurrence, for example if you want to have children. Insights into genetics are also increasingly influencing medical policy. For example, you can carry out preventive screening if you know that a hereditary condition entails an increased risk, or it can sometimes influence medication."

You also work as a doctor, what makes that combination valuable to you?

"As a doctor, I see many patients where there is a suspicion of a genetic cause. I have short lines of communication with the research group and this interaction is crucial to making better diagnoses. It gives me a lot of energy to be a doctor and to be able to help people this way. Because I can build the bridge with fundamental research, it can really help patients. Such short lines of communication are rare in genetics and research also benefits from this. Many researchers continue to work in a small niche, for example, how a few proteins interact. That is cool and also valuable, but it gives a much greater kick if research also has an application and can mean something for the patient."

There is a disease that bears your name. Can you explain that?

"In 2017, a girl came to our hospital with a very severe form of epilepsy. Her brain never fully developed and she only lived to be three years old. We knew that very severe epilepsy often has a genetic cause, but in the genes already linked to epilepsy we found no abnormality. We did find a defect in the UGP2 gene. That gene is in the same pathway as other genes involved in epilepsy, so we started to figure that out. Eventually we solved the puzzle within three years, which is quite fast. Via an international database, GeneMatcher, we found 40 children with exactly the same defect who also have this severe form of epilepsy.

Of course, we did not make up the name ourselves. That is what OMIM (Online Mendelian Inheritance in Man) does. They keep track of all genetic diseases, and they have to name everything. Elena Perenthaler is my PhD student, who is about to finish her dissertation. I think Elena is not always happy about the fact that a nasty disease is now associated with her name. I can also see the benefits. It helps us enormously to draw attention to the importance of this type of research and to create support for funding research into rare diseases."

What does this KNAW Early Career Award mean to you?

"I see it as a great recognition, and I am pleased that the value of our research group is really being seen. The short lines of communication with practitioners have been crucial, otherwise we would never have found Barakat-Perenthaler syndrome. There are still a lot of conditions to be recognised, so the 15,000 euros involved is a small drop in the ocean. Still, every euro counts. Something I would like to organise is a family day for parents of children with this severe form of epilepsy. It can mean a lot to relatives to get in touch with fellow sufferers and share experiences."

Barakat-Perenthaler syndrome

The story behind the discovery of this rare form of epilepsy reads almost like a thriller. The carriers of this disease all appear to have exactly the same defect in the UPG2 gene. This can only mean that all carriers are descended from the same person. By unravelling the family trees and genetic information of all the families involved, the search led back to a common ancestor 600 years ago in what is now Pakistan. The VOC had a trading post in that region and so it is possible that Dutch parents are still carriers of this hereditary predisposition. Read the whole story on Amazing Erasmus MC.