Understanding Genetic Susceptibility to Cytokine Storm Syndromes

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• Genomic Sequencing Identifies Mutations
• Interpreting Genetic Variants
• Clinical Case Examples
• Laboratory Validation Research
• Future Genetic Screening
• Full Transcript

Genomic Sequencing Identifies Mutations

Whole-exome and whole-genome sequencing are becoming more common in medical practice. Dr. Randy Cron, MD, explains that these advanced genetic tests can identify rare heterozygous mutations in asymptomatic individuals. These mutations may not cause disease immediately but can increase susceptibility to severe inflammatory responses from infections or other triggers.

Interpreting Genetic Variants

Finding a genetic mutation does not automatically mean it is pathogenic or disease-causing. Dr. Randy Cron, MD, emphasizes the importance of careful analysis. Computer algorithms can predict if a mutation is deleterious based on factors like evolutionary conservation or radical changes to protein structure. However, these in silico predictions are not perfect and require further validation.

Clinical Case Examples

Dr. Randy Cron, MD, shares a compelling case of an 18-year-old competitive athlete who presented with macrophage activation syndrome (MAS), a severe cytokine storm. Genetic testing revealed a single copy mutation in a perforin pathway gene. This mutation partially disrupted immune function. A colleague in Rome identified a patient with the identical mutation who had a similar clinical presentation. Intriguingly, both patients' fathers carried the same mutation but had never experienced a cytokine storm, highlighting the role of environmental triggers.

Laboratory Validation Research

Confirming the clinical significance of a genetic variant requires extensive laboratory work. Dr. Cron's lab studies these mutations in cells to see how they affect immune pathways like natural killer cell function. Collaborations extend to in vivo research. A colleague at the University of Pennsylvania helps study these mutations in genetically modified mice to observe if they contribute to a cytokine storm in a living animal.

Future Genetic Screening

The decreasing cost of whole genome sequencing makes widespread genetic screening a future possibility. Dr. Randy Cron, MD, speculates that it could someday replace individual disease screening at birth. However, major ethical and practical questions remain about data ownership and the clinical actionability of the information. The key challenge is knowing what to do with a genetic finding, especially when its manifestation is dependent on unknown future triggers.

Full Transcript

So more and more people also do genetic sequencing, whole-exome sequencing, whole-genome sequencing. These mutations are probably going to be identified in more and more people who are, of course, completely asymptomatic.

Perhaps it's something for people to be aware of, to know, and to see what is the meaning of those rare heterozygous mutations? Even though they don't carry the signature of a particular severe disease at the time, it just makes them more susceptible to certain insults via infections or other diseases.

Dr. Randy Cron, MD: Yeah, it's possible down the road that will be the case. I don't want to get Orwellian, or whatever. But it may be that instead of screening for individual diseases at birth, whether it's Tay-Sachs disease, for example, or something else, we will be getting whole genome sequencing.

Now who gets that data, who does what, that's not straightforward, and it's getting cheaper and cheaper every day. So it's not completely unheard of.

But analyzing that data, and then knowing what to do, even if you find a mutation. Just because you have a mutation, number one, it doesn't mean it's pathogenic or disease-causing. And number two, even if it is potentially contributing to disease, again, unless you're in the wrong inflammatory state, or you get the wrong trigger, it may not ever manifest itself.

For example, I had another patient who presented as a teenager with MAS or a cytokine storm, and she was 18. At the time, she presented and had been perfectly healthy. In fact, she was a competitive athlete.

But she got very sick with this. And she ended up having a single copy mutation in one of these genes in the peripheral pathway. And we took it back to the lab and showed that it kind of partially disrupted this pathway and made her immune system killing slightly less like we were talking about.

A colleague of mine in Rome had a patient with the exact same mutation who also had a very similar kind of cytokine storm. And it turns out that both patients' fathers carried the same mutation.

But they had never had a cytokine storm. So they went their whole lives, at least up to that point, without ever having it. Although I will say the Roman patient's father kind of ran an elevated serum ferritin, one of these markers of cytokine storm, even at baseline.

But I'm not sure how or why. And also, the father and the Roman patient, when the Rome patient was clinically well, their natural killer cell function was about half normal. So again, that's tolerated most of the time.

But again, just because you have that particular mutation, you may have to study all probably almost every single mutation. There are algorithms that will say, yes, this mutation is highly conserved among multiple species. And so that implies that it's very important not to change it, for example, from one amino acid to another.

Or they may say, it's such a radical change in amino acid that it will disrupt the shape of the protein or the function of the protein. And so it's much more likely than others.

But at this point, even those what we call in silico, or computer, probabilistic chances of these mutations being deleterious or harmful, are not perfect. And so my lab spends a lot of time actually trying to study them in cells back in the lab to see, if you introduce mutations, do they contribute this way.

And again, that's only in vitro. One of my colleagues at University of Pennsylvania has helped us by studying some of these in mice. And mice aren't humans, but we've learned a lot of immunology from mice, and that you can genetically manipulate them.

So that they may have a similar mutation or the same mutation, if it's conserved in humans and mice, and seeing do they contribute to a potential cytokine storm in vivo or in a living animal.