Headlining Rare Disease Diagnostics with Katrin Õunap

Katrin Ounap is an Estonian researcher focusing on clinical genetics and rare diseases. She investigates the genetic causes in Estonian children with unclear diagnoses. Her main clinical interest has been metabolic diseases. She has consulted and treated many patients with genetic syndromes and chromosomal diseases too.

Katrin was one of the people who introduced newborn phenylketonuria screening in Estonia. Today she is a professor in clinical genetics at the Institute of Clinical Medicine at the University of Tartu. She is also Head of the Department of Clinical Genetics at Tartu University Hospital and the guest of the latest episode of the Beyond BAFF podcast.

Get a glimpse into the life of a clinical geneticist specializing in rare diseases and hear the full story here.

When you were in the U.S. and doing research there, were you still connected with Estonia and investigated Estonian diseases?

Yes, we actually started the cooperation back in 2016 when Harvard University was nominated to be a Center of Mendelian Genomics in the U.S. to improve the diagnostics of rare diseases, and they also offered Estonia to be a partner for solving unresolved cases.  So it was very logical to be there as part of the BAFF program in 2018 and to do research there on the spot.

At that time, we had already recruited more than 120 families to be reanalyzed because, nowadays we have very excellent techniques to investigate human, genetic information, but at the same time, we can solve cases in a clinical setting only in one photo frame.

So, we continued to do this research study in cooperation with the Broad Institute at Harvard University. We reanalyzed the genomic data with the help of a platform called Seeker, which is a special program invented by their team. In addition, we also implemented genome sequencing for unsolved cases and, RNA sequencing, which is called also by our name—transcriptomic analysis.

Finally, we also did a pilot study in selective cases together with a U.S. company analyzing more than 800 metabolites in patient plasma samples.

And now we know that in all of those unsolved cases, we solved, in addition to the previous group, 60 percent of the cases. We still cooperate with them in inventing new techniques and looking at all the data together.

And are you the only person who focuses on this? How many people are there who do the same thing?

I have my own research team that I'm leading it. When I came back from the U.S., I also applied to the Estonian Research Council to get funding, which helped create this secret program locally in Estonia.

We continued recruiting patients for the research study, and we analyzed an additional set of almost 200 families in Estonia using the knowledge I gained in the U.S. We also still have regular meetings with U.S. researchers and discuss complicated cases together.

Which specific diseases are you focusing on? You say rare diseases, but how do you distinguish between rare diseases and the ones that are not?

By definition given by European and American doctors and researchers, the disease is rare when it’s less frequent than 1 in 2000. But there are many subcategories. If you’re looking at the number 1 in 2000, it's rather common, so we also have categories like ultra-rare diseases, which are less than 1 in 100,000 or less than 1 in 1 million. In some cases, we see some diseases really very seldom.

But if you are looking at it as a group, there are more than eight thousand rare diseases known nowadays and most of them are genetic. For example, in Estonia, at least four to six percent, of the population may have some type of rare disease and it's a quite large number. It's approximately 80,000 people.

And a more complicated question is the one I'm always asking my students—what do you think, how many new diseases will we discover every year? This number is still rather large. It's approximately 250-300 new disorders. So that's why it's very important to do such kind of reanalysis that we are doing in a research setting because a laboratory could write a report for a patient today but then later, a research group may discover a new gene after two weeks, and it won’t be reported at the right time.

You said that you focus on Estonian patients and Estonian diseases. Does it mean that you don't exchange information and findings with Latvians and Lithuanians, or is it actually the opposite?

You have to cooperate actively with other groups because if you discover a new gene variant that looks very interesting and you think it may be a gene causing a new disease, then you have to share these findings and use a matchmaking or matchmaker platform.

We are not writing the patient’s name there, it's coded, of course. And when I match with other researchers in any country who have discovered the same gene variant, we exchange information about this variant and also clinical findings and we try to find a partner who is interested in research to prove that this gene is disease-causing.

Sometimes you can collect only clinical findings and look where those variants are located in the gene. Sometimes you can model them or do functional investigations. It depends on the gene function and other factors, and it's very interesting.

I have matched with some researchers for many years and met them for the first time only recently at one European Reference Center network meeting.

If we take a step back and look at the big picture, how did you get started in research? Why did you decide that you want to go so deep into rare diseases?

It's difficult to say. I started my career more than 30 years ago. I was trained initially as a pediatrician, and the hospital just offered me to specialize in clinical genetics because, at that moment, it was a very underdeveloped subspecialty for different reasons. And I just said yes, I followed the flow. For most of my life, I have followed the so-called flow.

So it just happened that I turned to specializing in genetics initially in Moscow and then in Finland and Germany.

When you think about the flow that brought you here and that you've followed, what do you wish to see happening in your field in the future?

We have started new research projects with the team—we are trying to combine different omic methods in Estonia locally and creating a new machine for doing metabolome and proteome analysis.

So it's a very difficult task now to work out the technology for proteomic analysis, which nobody has done before. Our vision is to be able to do this analysis without gathering different biological samples from patients.

Right now, we have to analyze amino acids, organic acids, sugars, or fatty acids separately. But if we build up this new technology, we can do just one untargeted metabolome analysis in the patient, and we can answer immediately after one analysis if there is any suspicion of metabolic diseases.

And if you look back today to your year in the U.S., what were the biggest takeaways for you?

Definitely knowledge and skills on how to build up a system. Contacts are also very important. As I said, we are actively exchanging information and I know that I can always ask for their advice. 

Want to be notified when new episodes are released? Sign up for the Beyond BAFF podcast newsletter.