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Dutch University hospital Radboudumc finds genetic mutation as a reason for lack of defense against corona

“The virus can just take its course because TLR7, which is supposed to identify the intruder and then activate the defense, is hardly present.”
Bart Brouwers

Two brothers from the Dutch village of Beek en Donk were 29 and 31 years old when Corona hit them hard. At the first peek of the pandemic in the Netherlands, they were proof that COVID-19 did not only affect the elderly. The brothers ended up in intensive care, where they were kept in an artificial coma. The eldest eventually managed to survive, the youngest did not.

The distressing events were the beginning of a search by doctors and geneticists of the Nijmegen Radboudumc for genetic factors in a human’s defence. Their research makes it clear that TLR7 – Toll-like receptor 7 – plays an essential role in the disease process. A finding with potentially major consequences, with which Radboudumc came out yesterday in a publication in JAMA. There is good hope that this might even result in a treatment for new Corona patients.

In the wave of COVID-19 patients that engulfed Dutch hospitals in the first half of 2020, an attentive physician from the clinical genetics department of the Maastricht MUMC+ found something remarkable, which would be the start of important scientific research at the Radboudumc. Two young brothers within the same family who became seriously ill because of the SARS-CoV-2 virus and had to go to the ICU for ventilation. One of them died from the consequences of the infection, the other recovered. Remarkable, because it was mainly elderly people who were affected by the virus and in this case two brothers under the age of 35 from the same family.

Genetic factors

“In such a case you immediately wonder whether there are also genetic factors involved,” says geneticist Alexander Hoischen. “Getting sick from an infection is always a combination between – in this case – the virus and man’s defence. The fact that two brothers from the same family become so seriously ill may, of course, be a coincidence. But it is also possible that a congenital abnormality in their defence played an important role. We started investigating the latter with our multidisciplinary team in the Radboudumc.”

One X-chromosome

From both brothers, all genes with a function (the exome) were mapped. Subsequently, a possible cause is searched for. Cas van der Made, a Ph.D. student at the Department of Internal Medicine: “In doing so, we mainly looked at genes that play a role in the immune system. We know that many of these important genes are located on the X chromosome. Women have two X chromosomes; men have a Y chromosome in addition to the X-. So men only have one copy of the genes on the X chromosome. If something is wrong with that, there is no second gene that can take over that role, as there is in women”.

“So it looks like the virus can just go ahead because the immune system doesn’t get a message that the virus has gotten in.”

During that research, the gene encoding for the Toll-like receptor 7, or TLR7 for short, soon came into the picture. There are several TLR genes, but they all have in common that they play an important role in recognizing pathogens and activating the innate immune system. Hoischen: “A few letters were missing from the genetic code of that TLR7. As a result, the code could not be read properly and hardly any TLR7 was made. Until now, the function of TLR7 has never been associated with a congenital immune disorder. But suddenly, we now see that TLR7 is apparently essential to identify this coronavirus. It seems as if the virus can follow its course because the immune system does not receive any message that the virus has entered. Because TLR7, which is supposed to identify the intruder and then activate the immune system, is hardly present at all. That could be the reason for the serious course of the disease.”

Extra confirmation

Quite unexpectedly, the doctors and researchers in the Radboudumc again had to deal with two seriously ill brothers with COVID-19. The two were even younger: 21 and 23 years old. Both also had to go to the ICU for ventilation. “Then the question of the role of the genes is even more obvious,” says Hoischen. “We carried out the same research with these two brothers, again using the unique ‘rapid-exome’ diagnostic route. This time we saw no deletion, no loss of letters, but only a single writing error in the TRL7 gene. The effect is the same because these brothers also do not make TLR7 sufficiently effective either. Suddenly we had four young people with a defect in the same gene who had all become seriously ill because of the SARS-CoV-2 virus.”

Essential role in the defense

Van der Made and his colleagues have figured out how the mechanism works. “Once activated, TLR7 ensures the production of so-called interferons, signal proteins that are essential in the defense against viral infections”, says van der Made. “This immune response is perhaps all the more important in the fight against the SARS-CoV-2 virus because we know from the literature that this virus has tricks to reduce the production of interferons by immune cells. When mimicking an infection with the coronavirus, we see that the immune cells of the patients without a properly functioning TLR7 hardly react and that hardly any extra interferons are produced. These tests show that the virus seems to have free rein in people without a properly functioning TLR7 because it is not recognized.”

Consequences for the treatment

“Due to the serious illness with two brothers in two families, from which one of the young men died, we have come on the trail of this condition,” says Hoischen. “It appears to be a very specific abnormality, an immune deficiency, mainly related to this coronavirus. None of the four men had previously suffered from the defense or immunity. It’s the first time that we’ve been able to connect a clinical picture so strongly to this TLR7.”

“This discovery not only gives us more insight into the fundamental functioning of the immune system but may also have important consequences for the treatment of seriously ill COVID-19 patients”, says immunologist Frank van de Veerdonk. “The substance interferon can be given as therapy. It is currently being investigated whether giving interferon to COVID-19 can indeed help.”

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About the author

Bart Brouwers is co-founder and co-owner of Media52 BV, the publisher of innovationorigins.com.

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Research at Radboudumc: "Corona can just take its course because TLR7, which is supposed to identify the intruder, is hardly present."

Dutch genome deciphered

The family tree of the Dutch people has been deciphered by researchers at 5 Dutch universities under the leadership of Prof. Cisca Wijmenga of the UMCG in Groningen. The early history of the Dutch can be re-written and diseases can be better predicted. The research is described in a Nature Genetics article published yesterday.

`Paul de Bakker, Cisca Wijmenga and colleagues report on The Genome of the Netherlands Project, including whole-genome sequencing of 769 individuals of Dutch ancestry from 250 parent-offspring families and construction of a phased haplotype map. Their intermediate-coverage population sequencing data set provides a complementary resource to other publicly available data sets, including the 1000 Genomes Project.´

See also the UMCG press release below.

Whole-genome sequence variation, population structure and demographic history of the Dutch population
The Genome of the Netherlands Consortium
Published online: 29 June 2014| doi :10.1038/ng.3021

Whole-genome sequencing enables complete characterization of genetic variation, but geographic clustering of rare alleles demands many diverse populations be studied. Here we describe the Genome of the Netherlands (GoNL) Project, in which we sequenced the whole genomes of 250 Dutch parent-offspring families and constructed a haplotype map of 20.4 million single-nucleotide variants and 1.2 million insertions and deletions. The intermediate coverage (

13×) and trio design enabled extensive characterization of structural variation, including midsize events (30–500 bp) previously poorly catalogued and de novo mutations. We demonstrate that the quality of the haplotypes boosts imputation accuracy in independent samples, especially for lower frequency alleles. Population genetic analyses demonstrate fine-scale structure across the country and support multiple ancient migrations, consistent with historical changes in sea level and flooding. The GoNL Project illustrates how single-population whole-genome sequencing can provide detailed characterization of genetic variation and may guide the design of future population studies. full text in Nature Genetics

Press release: The Genome of the Netherlands

Researchers from 5 Dutch universities have been working together under Prof. Cisca Wijmenga from the UMCG to compile a genetic profile of the Netherlands. ‘This profile will help us to identify connections between genetic variation and disease. The genealogy of the Netherlands will also provide information about historical large-scale migrations’, explains Wijmenga. The researchers’ findings are published in today’s edition of Nature Genetics.

The researchers mapped the DNA sequences of 250 family trios comprising two parents and a child from all around the Netherlands. This is the first time that genes from so many healthy Dutch people have been analysed with such precision.

Significance to genetic research

‘The Genome of the Netherlands project represents a huge step forwards in our research into the specific genes that play a role in chronic illness or diseases affecting the elderly’, says project leader Prof. Cisca Wijmenga from the University Medical Centre Groningen. ‘Thanks to this project, we are now able to focus our research on specific pathogenic genes much more quickly than in the past’. She expects that their work will be particularly significant for the field of clinical genetics. ‘The Genome of the Netherlands provides a catalogue showing which variations in DNA are tolerated and which can lead to a disease. If we are able to combine this information with data derived from gene expression, our predictions will be even better’.

Information about gene expression and other ‘omics’ data was also collected during the Genome of the Netherlands project. Wijmenga: ‘This will enable us to identify real connections between variations in our DNA and their impact on all kinds of molecular systems. The Genome of the Netherlands is a prime example of big data research, in which the huge amount of data collected is helping us to detect and understand unexpected connections.’

Mutations not necessarily pathogenic

In one of the more striking findings from the Genome of the Netherlands work, researchers found that every participant had an average of twenty mutations that they had previously thought would cause a rare disease. ´The variation in our DNA is far greater than we expected. This means that the link between differences in DNA and the development of disease, for example, is much more complex than we originally thought’, explains researcher Prof. Paul de Bakker from the UMC Utrecht. ‘We found numerous mutations that we had always assumed would cause disease. But the people taking part in the Genome of the Netherlands are all in good health, so it seems that these mutations do not necessarily cause disease.’ For example, two of the people examined were found to have a mutation that should have led to a rare metabolic disorder (Alpha-1 antitrypsin deficiency) at an early age; however both subjects were perfectly healthy.

Older fathers

The research also confirmed another observation. Children of older fathers have more mutations in their DNA. This may explain why these children have a higher risk of developing certain diseases.

Migrations and floods

The study provided interesting information about historical migrations in the Netherlands. The traditional view is that people gradually colonized the Netherlands thousands of years ago, starting in the south and moving northwards. This should be reflected in more genetic variation in the south and less in the north. Although the researchers noted this trend, another analysis showed the exact opposite, seeming to show that the Netherlands was colonized from the north downwards. In order to link up these differing genetic results, the researchers produced highly refined models of migration patterns. According to the models, several migrations in various directions took place in the period between 4,000 to 500 years ago. The patterns could be linked to recorded events in history, such as major floods and the mass migrations that followed.

‘It just goes to show how much unique information about our ancestors is hidden in our DNA’, says De Bakker. ‘But the most important aspect of our project is to try to understand which genes play a part in disease.’

Unique collaboration

This unique, large-scale research project was set up by BBMRI-NL, the Dutch organization for biobank collaboration. Programme director Gertjan van Ommen: ‘The Genome of the Netherlands is unique in the Netherlands and a flagship project for BBMRI-NL. Exchanging information for biomedical research is one of the mainstays of BBMRI-NL and the Genome of the Netherlands has made serious progress in this respect. It has not only produced some surprising results, but it is also acting as a facilitator for other innovative research projects, both at home and abroad. It has proved itself to be the perfect long-term investment.’

The study was carried out by researchers from the UMC Groningen, UMC Utrecht, Leiden UMC, VU Amsterdam, AMC Amsterdam, UMC St. Radboud Nijmegen, the Centre for Mathematics and Computer Science in Amsterdam and the Erasmus MC in Rotterdam. Groups from various other countries also worked on the project.

Unraveling the genetics behind complex traits ]]>