Discovery of a new syndrome brings answers to hundreds of patients with developmental delay

Clinical geneticist Stefan Barakat of Erasmus MC is a bit surprised that something like this could still happen in his field. The team from the Department of Clinical Genetics and international colleagues discovered a genetic syndrome that explains the severe developmental delay of a large group of patients. 

Until now, families and doctors were left in the dark about the cause of the developmental disorder, which is characterized by intellectual disability, epilepsy, autistic features, and other symptoms. This uncertainty is not uncommon, as routine diagnostics leaves sixty percent of developmental disorders unexplained. 

Spectacularly large group

The newly discovered syndrome is estimated to provide answers for 0.4 percent of patients with previously unexplained developmental disorders. “That may sound like little, but worldwide it involves hundreds of patients, and that is probably just the tip of the iceberg. In the field of rare diseases, that is a spectacularly large group,” Barakat explains. For some patients, this has even ended a twenty-year search. “A diagnosis means recognition and acknowledgment, which is very important for patients and their environment. Additionally, a diagnosis is the starting point for, whether or not future, treatments.”

Shortly after the discovery of the syndrome, which was named ReNU syndrome, a patient association was founded. 

‘We are increasingly aware that abnormalities in non-coding DNA can also cause disease’

The discovery of the ReNU syndrome was made possible by a technique that has accelerated in recent years.  Whole genome sequencing, or WGS: a comprehensive test that reads the entire DNA. “Until a year ago, in diagnostics we only looked at the pieces of DNA that code for genes and ultimately make proteins. That is only two percent of the entire DNA. With WGS, we also look at the remaining 98 percent of the DNA. We are increasingly aware that abnormalities in those parts can also cause disease,” Barakat explains. His research group at the Department of Clinical Genetics specializes in this so-called non-coding DNA. Since a year ago, Erasmus MC has also been using WGS in routine diagnostics. 

First Dutch patient

It was British scientists who first discovered the ReNU syndrome. They performed the WGS test on the DNA of over 8000 patients with an unexplained developmental disorder. The same hit often came out. 46 patients had exactly the same mutation in RNU4-2. That is a gene in the non-coding DNA, which can only be found with WGS. When the patients also had similar symptoms and physical characteristics, it was clear: the British had found a new genetic syndrome, and this was also independently confirmed by an American group. 

The British contacted Barakat and his colleagues because they also work on non-coding DNA. The Erasmus MC researchers then delved into the WGS data of their patients with an unexplained developmental disorder and identified the first Dutch patient with the ReNU syndrome. A growing group of international scientists, together with the Erasmus MC researchers, investigated through which mechanism the abnormalities in the non-coding DNA lead to the ReNU syndrome. 

Later, dozens of patients with a mutation in a similar non-coding gene, RNU2-2, were identified. These patients have similar symptoms to patients with the RNU4-2 mutation, and this abnormality can also only be found with WGS. 

The team behind the discovery. Sitting: Rachel Schot (data analist Discovery Team) and Frank Sleutels (laboratory specialist clinical genetics). Standing, first row, left to right: Federico Ferraro (PhD student bioinformatics/Innovation team), Geert Geeven (bioinformaticist diagnostics clinical genetics), Stefan Barakat (clinical geneticist) and Sarina Kant (clinical geneticist). Upper row: Karin Diderich (clinical geneticist) and Christophe Debuy (PhD student Discovery Team). Photo by Ruud Kopppenol

Barakat is pleased that a medical mystery has now been solved for a large group of patients. Looking back, it might have even happened earlier. “With the knowledge we have now, I think: how could we have missed this? If you look at photos of the patients, they have very similar appearances. My colleague clinical geneticist Sarina Kant recognized a patient she had been following for a long time without a diagnosis based on the physical characteristics of the ReNU syndrome. She turned out to have a mutation in RNU2-2.” 

Still, it is not illogical that this syndrome remained hidden for so long in what Barakat calls “the dark matter of our DNA.” Various things had to come together: WGS had to be introduced into diagnostics, and insights from fundamental research into non-coding DNA had to come together with the knowledge and experience of doctors from the clinic. Barakat: “This is really a team effort between fundamental research, discovery and innovation teams, bioinformaticians, diagnostics, and patient care that shows how valuable it is to dig into the non-coding DNA.”