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Jeffrey J. Swigris, DO, MS: Hello. I'm Dr Jeff Swigris. Welcome to season 2 of the Medscape InDiscussion podcast series on idiopathic pulmonary fibrosis. Today we are going to discuss the topic of genetics of pulmonary fibrosis, and we're so lucky to have my guest, Janet Talbert, with us today. Janet is a senior associate in the Department of Pediatrics in the Division of Medical Genetics and Genomics at Vanderbilt University Medical Center in Nashville, Tennessee. She also serves as a genetic counselor in the Division of Pulmonary and Pediatric Genetics. Janet, welcome to the podcast.
Janet Talbert, MS: Thank you for having me on this podcast, Dr Swigris. I'm really honored to be here.
Swigris: Janet really is one of the experts in the genetics of pulmonary fibrosis so we're very lucky to have her here today. Before we get into the nitty-gritty, Janet, tell our audience how you became interested in genetics and genetic counseling, particularly in the area of pulmonary fibrosis.
Talbert: If I had to encapsulate that into one idea, I would say it was pulmonary fibrosis itself. I had already been tinkering with the idea of becoming a genetic counselor. I had a background in working in genetic laboratories, research, and even forensics. I was applying to the field and while I was waiting, I started working at National Jewish Health in Denver, Colorado, on a study for familial pulmonary fibrosis, or FPF.
I was drawing pedigrees, I was taking family histories, and I couldn't really answer everyone's questions about their risk or what it was going to mean for them if a gene was found. I realized I was actually doing the work of a genetic counselor without the proper training. So that propelled me and sealed my decision to go into that field.
Swigris: And we're really lucky you did. Janet has improved knowledge of genetics in our field and really advanced our understanding. She has helped so many patients and families and practitioners, like myself, to give us some of the knowledge that patients and their families are looking for.
Patients often will ask, "Why me? Why did I get this?" And in my simplistic view, being a clinical investigator, not a genetic researcher, or a basic scientist, I tell patients and their families that the way we think about pulmonary fibrosis now is that there are three things that come together to allow pulmonary fibrosis to develop. One is aging, and that's not to say all patients with pulmonary fibrosis are old or that as we age, we are going to get pulmonary fibrosis; but there's something about the lung getting older that predisposes to the development of fibrosis. There's something about the lung getting injured that predisposes to the development of pulmonary fibrosis. And in my simplistic view, I say "genetic programming" — the way the lung in an individual patient is programmed to respond to that injury, predisposes to the development of fibrosis.
We want to hear a little bit more about genetic programming, so talk to us, if you would, Janet, about our current understanding of not this broad-view genetic programming but the actual genetic basis of pulmonary fibrosis.
Talbert: Well, the current understanding is really just like the disease itself; it's very complicated. Namely, it's not a single gene disorder like cystic fibrosis or muscular dystrophy. It's not even a single class of genes but rather a conglomeration of various types of genetic risk combined with or without environmental components. So genes have been discovered that strongly run in a subset, a very small subset, of families.
Pulmonary fibrosis can also cluster in families without a genetic identification, without a gene that we know of. Or it could just be common genes that we all share that predispose but may not directly cause that may contribute, along with some kind of environmental exposure.
And on top of that, you mentioned aging. Our genes break down as we get older, just like a car. We have to keep our car healthy, right? So for us, that's exercising, eating right, staying away from toxic environments. Some of the genes we've discovered are involved with the aging process. So that makes sense as well.
Swigris: It seems like this field is rapidly evolving. I remember when I first started out, we had no clue about the specific genes that predispose or increase the risk for pulmonary fibrosis. So talk to us about the past decade and some of the specific genes that have been discovered that are now linked with pulmonary fibrosis.
Talbert: In the past decade, and maybe even the past two decades, a couple of things have happened. We've mapped the human genome. Our technology has become faster, quicker, and cheaper to run genetic testing, to discover more genes. Then what we've done by studying families, enrolling families into trials and looking at their DNA, is that we've discovered several genes and two pathways that seem to strongly run in a very small set of patients and families. We don't have an explanation for every family.
One of those pathways is the telomerase pathway involving our telomeres, which are involved in aging. What's happening is they're prematurely aging. The other pathway is surfactant, which we typically see in childhood, and we think of childhood interstitial lung disease as a little bit different and separate from the adult-onset type. There are some genes that can run in families, but it's a very small subset of the subset of families.
And then we've found through genome-wide association studies where we compare healthy people, or we think they're healthy, to people with IPF or pulmonary fibrosis. When we try to see what's common and what's not, we find certain genetic changes that seem to coincide more with the patients with disease than with patients without. But they are common, meaning that even healthy people are walking around with those changes and they will never get pulmonary fibrosis. Those are called common variants. I would say this has all really ramped up in the past decade. We've learned these things, but we don't have 100% of our patients covered from a genetic standpoint.
Swigris: Can we circle back around to the telomere story? I think of telomeres sort of as caps on the end of our chromosomes. As our cells divide and DNA replicates or makes copies of itself, these telomeres are supposed to stay a certain length relative to our age.
They get shorter as we age. We have an enzyme program that is meant to keep our telomeres a certain length for our age. And if the telomeres are inappropriately short for one's age, that is associated with certain abnormalities, one of which is lung fibrosis.
One, is that the right way to think about that? And two, can you speak more to the telomerase pathway and this telomere pathway in terms of its link with pulmonary fibrosis?
Talbert: Yes. Everything you said was very well put. The telomere length does shorten over time. An older person's telomere lengths in their cells are going to be shorter than a baby's telomere lengths. That's supposed to happen. It's like a reverse growth curve. Its link with pulmonary fibrosis was discovered in other premature aging syndromes where we would see bone marrow failures and liver cirrhosis of unknown cause, bone fractures, osteoporosis, certain head and neck cancers, immunodeficiency, and these were all linked by these genes that were in that telomerase pathway.
Telomerase is an enzyme, and an enzyme is made by genes. DNA is our code of letters, and it spells out for certain genes to create proteins — in this case telomerase. Telomerase carries out a function, which is to keep that process intact and regulated over time. When there is a pathogenic variant — which used to be called a mutation, but the language has changed to "pathogenic disease-causing variant change in a gene" — that process is disrupted.
There are a host of genes, probably up to 16 now, that have been found across these telomere biology disorder spectrums, and pulmonary fibrosis is in that spectrum. Some people with telomere biology disorders and pathogenic variants are affected at a younger age. The older ones tend to get liver cirrhosis or the pulmonary fibrosis diagnosis, but it can span the lifetime. And so when I take a family history, a lot of times I will ask about those spanning from childhood all the way to older age.
Swigris: That's really important information for us as practitioners. So you taught us, when you were here at National Jewish Health, when the telomerase story was really just being discovered and solidified, that if we have a patient with pulmonary fibrosis, we ought to be asking questions about their history and their family history. And you mentioned a few of them, but I want to make sure that for the practitioners out there, we hear from an expert.
So we should ask about premature graying of the hair. I would love to have you comment on that because I've heard different age cutoffs for that. We should ask about any issues with the liver, any issues with bone marrow, and funny anemias or low blood counts, nontraumatic fractures, head and neck cancers.
Are there other things that we ought to be asking about? And then circle back, if you would, to the premature graying of the hair.
Talbert: Yes. Premature graying of the hair is my least favorite question; I'm only really impressed if it's happening under the age of 30. I'm especially impressed if it's in the teens or early 20s. There are so many other reasons to have gray hair; there are other genetic conditions or it could run in families. It could be separate from the telomerase pathway. So one doesn't always equal the other.
And because it's so easy to see, it's an easy go-to, but they don't equal each other. I've had families with telomerase mutations that don't have premature graying. So it's definitely something to keep in mind to really think about that age of onset. And if I even go back in my own history, I could have said I had a gray hair at 28 years of age.
Bone marrow failures, liver cirrhosis, alopecia… The classic triad was oral leukoplakia, dysplastic nails, and a lacy reticular pattern around the neck. But most people don't even have that. They might present only with pulmonary fibrosis.
Because your whole genome is throughout your entire body, these genes are expressed in different tissues. And therefore, for one person, it could present as pulmonary fibrosis. For another person, it could be myelodysplastic syndrome, or it could just present as pulmonary fibrosis in a family in isolation.
It's important to recognize that there are other extrapulmonary manifestations, but the lack of them doesn't exclude the possibility of a telomerase mutation. Even in our sporadic patients, we can see the same type where one person has IPF, but if you start looking at their family, you see some of these bone marrow failures, liver cirrhosis, other indications that might enrich for a gene mutation in the family. And about 10% of the time we can find it even in sporadic IPF.
Swigris: I get questions a lot where patients will come in and say, "How did I get this?" or "What did I do?" or "What tests can be done?" I'd like you to comment on that. If I have a patient who comes in, they're diagnosed with what looks like idiopathic pulmonary fibrosis. I take a family history. Obviously, my family history is not going to be nearly as extensive as yours. There's no suggestion of telomerase abnormality based on those questions that you just mentioned. But the patient says, "I want to get genetic testing" or "Should I get genetic testing?" How should we respond to that patient?
Talbert: That's a great question and one I get often. I think if they desire genetic testing, that should be an option for them. You should explain the limitations of actually finding something. Earlier I had said it's about a 10% pickup rate in sporadic IPF. In families, it's about 30%. And the more of those extrapulmonary features you have, it can go up as high as an 80% chance of finding a pathogenic variant.
Part of counseling is explaining to them the limitations of genetic testing and how we don't know everything right now. Some of the tests that we can do won't answer that question, but it doesn't mean that it doesn't have a genetic component, that we've ruled out the genes we can currently test for. I've been doing this for 21 years, and in those 21 years, we started out with two genes and then five genes, and now we're up to about 13. And we continue to find new genes as we do studies and learn more about the genome and what these genes are doing and these pathways.
Also, our technology, even though it's cutting-edge, only looks at a certain portion of genes when we do testing. We think it's the important parts, but we could learn in a year or two that there is a very remote place in the genome that we didn't know existed that happens to impact the development of pulmonary fibrosis. And then we have to go back and retest people.
So genetic testing, to me, is sort of like radiology; it's a snapshot in time. And then our technology increases, we get better, we get more refined, we learn more, and we can take another snapshot at a different time.
Swigris: One thing you said that I want to reinforce and highlight for the audience here is that if a patient wants genetic testing and you decide to pursue genetic testing, it is critical that a genetic counselor be involved, because as you said, Janet, you have the expertise.
Patients need to know what we can actually test for and patients also need to know the implications of the results: "Okay, if you have genetic abnormality X, Y, or Z, this is what it means. But if you don't have any identifiable genetic abnormality at this time, this is what it means."
Talbert: Yes, absolutely. A patient should have that conversation with a genetic counselor or someone knowledgeable who has that expertise, such as a physician who specializes in genetic forms of pulmonary fibrosis, because there are a host of other questions that come behind that.
If we were to find a genetic cause in a family that has implications for other family members, what can we do? What does that mean for their children, their grandchildren, their siblings? It takes someone to think beyond just the patient in front of them, to think of the patient as also a family because genes are shared by their family members. That takes some special conversations as well.
And then we think about clinical utility. At the end of the day, what we'd like to do with genetics is have some action to take when we find this. Right now that is very limited for pulmonary fibrosis. So we can find the information, but we don't know exactly what to do with it at this point. And that can cause some areas of anxiety or even depression or feelings of not being in control. Some people find it empowering too, but they should be in the care of people who have an expertise, like a medical geneticist, a genetic counselor, or someone who's in this field, specifically with genetic knowledge.
Swigris: Again, just to reinforce that, this is a very individualized decision and one that should be made with an expert because, as Janet said, some patients are going to want to know and other patients are not going to want to know. Many of my patients who would like genetic testing say they're doing it for family members and so forth, but it's a very individualized decision and should be made with the experts.
Moving forward, can you talk to us about a vision for how genetics and genetic studies might contribute to the development of therapies for lung fibrosis? Where do you see avenues for advancement in our field, and where we might be going over the next decade or two?
Talbert: Well, first of all, I think this is a very undertested population. The more we test our patients and their family members, the more we're going to learn. There's been some hesitation for testing because of that lack of clinical utility or maybe cost, which has come down immensely. We can't do anything about fear. If someone doesn't want to test, we support that as well, especially in my field of genetic counseling.
But the more we test, the more we're going to learn, and we're going to drive knowledge and possible therapies. Some of the common variants could be used as targets in clinical trials. If we know these pathways like telomerase or surfactant, we know what enzymes are not being produced enough, and maybe we could supplement those. The field of medical genetics has been doing this for a really long time, since probably the 1970s with metabolic disorders. And now that's moving into cancer therapies and neurologic therapies. So I see that we could do that with pulmonary fibrosis.
Pulmonary fibrosis and its genetic underpinnings are no different than those of Alzheimer's or cancer or neurologic disorders, which are all other diseases of aging. Those are farther ahead than us and some of that is because the genetics haven't been as emphasized. So I think if we start testing more, even clinically, not just in a research setting, we can start to open up the knowledge and maybe create clinical targets for those genes.
Swigris: Is genetic testing covered by insurance? And if it's not and patients are paying out of pocket for the 13 genes or however many we can test for, what's the cost going to be for a patient?
Talbert: Genetic testing is not always covered by insurance because of the lack of clinical utility that they see. However, there is starting to be more clinical utility. For instance, the lung transplant teams are starting to utilize telomere length and telomere pathogenic variants as part of their workup, mainly for posttransplant treatment and immunosuppression regimes. Because of that, there are insurance companies that may be able to pay.
I can't speak per insurance company, but if a patient does have to pay out of pocket, we can test for panels of genes for less than $500. It depends on the lab. And again, that's why a person with expertise in genetics, like a genetic counselor, should be involved so that they can pick the right tests for the right patient. We also take cost into account as one of those limiting factors.
Swigris: Janet mentioned that the lung transplant field is testing telomere length because there are emerging data to suggest that patients with really short telomeres — and the cutoff varies less than the 10th percentile or maybe less than the 1st percentile — are at increased risk with immune suppression of bone marrow abnormalities, if I'm not mistaken. We're even seeing this creep into the interstitial lung disease field a little bit, at least in raising the question of the safety of immunosuppressive therapy in patients with shorter telomeres. So stay tuned for that, as that story is really emerging.
Talbert: In addition, the identification of pathogenic variants in genes for other family members who are then at a predisposition could implicate those patients to seek care earlier and possibly catch fibrosis before it begins. Even though having a pathogenic variant does not guarantee that they will develop pulmonary fibrosis or any of the other extrapulmonary manifestations, it confirms their risk in the family, and then we could possibly screen them.
For instance, there are studies out there that are looking at first-degree relatives of familial pulmonary fibrosis patients and scanning with CT scans and breathing tests to detect early disease. If we knew their genetic profile and knew that they carried a pathogenic variant, that would mean we would need to follow them closely clinically as well.
Swigris: That's really important information. I know that you aren't necessarily the one who's ordering CT scans and breathing tests, but you certainly are in discussion with researchers and potentially practitioners who are.
So right now, June 2024, what's the practice if I have, let's say, a first-degree relative of a patient with pulmonary fibrosis? This first-degree relative has a genetic variant that predisposes them to the development of lung fibrosis, but they're currently asymptomatic. What should we be doing for them? Or what have you seen some of the practitioners in-the-know doing?
Talbert: There are no established guidelines. However, some practitioners would do baseline screening, say, maybe after age 40. And again, that's anecdotal. There are no guidelines that state that, but we actually don't know when this disease starts. That's part of our clinical trials of looking at these family members asymptomatically and seeing if there's early disease there, and then watching them. Because even if they have that pathogenic variant due to reduced penetrance, they could have an attenuated form, or they may never develop pulmonary fibrosis in the first place. So they may screen them with pulmonary functions and baseline CT scans and do that every several years.
Swigris: So for practitioners who do not have a genetic counselor on campus or access to one, should we just find a center and send those patients there? Or are there other resources that you might recommend for folks who aren't near an academic center, for example?
Talbert: The field of genetic counseling lends itself well to remote and telehealth options. There are several telehealth companies across the US that are licensed in every state and can do telehealth either by telephone or video. [They can] work with that patient to pick the right tests for them, order it through their local physician, possibly, or even order it for them and get results back. Everything can be done remotely with genetic testing, in addition to professional bodies like the American College of Medical Genetics and Genomics, the National Society of Genetic Counselors, and the American Board of Genetic Counseling, where you can locate individuals with genetic expertise.
Swigris: That's great information. Thank you, Janet. Today we were so lucky to have Janet Talbert with us to talk about the genetics of pulmonary fibrosis.
Here's a high-level recap. There are genetic variants that we know are associated with lung fibrosis. Janet reminded us of two critical pathways, but the field is certainly emerging, and it seems like more and more genes are being discovered every day. The two pathways are the telomerase pathway and the surfactant pathway.
Most importantly, work with your genetic counselor for patients who are thinking about genetic testing. Genetic testing, in my opinion, should never be done without the help of a genetic counselor because it is really important for patients and their family members to know what we can test for, what we cannot test for, and what the implications are for either a positive test (finding a genetic variant) or negative tests (not finding a genetic variant).
Janet, thank you so much for being with us today. We really appreciate your knowledge and expertise.
Talbert: You're welcome. Thank you for having me. It's been a pleasure.
Swigris: To the audience, thank you very much for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on idiopathic pulmonary fibrosis. As always, I'm Dr Jeff Swigris for the Medscape InDiscussion podcast.
Listen to additional seasons of this podcast.
Resources
Pulmonary Fibrosis Predisposition Overview
Lung Fibrosis, Premature Graying, and Macrocytosis
Idiopathic Pulmonary Fibrosis Is Associated With Common Genetic Variants and Limited Rare Variants
Idiopathic Pulmonary Fibrosis and the Role of Genetics in the Era of Precision Medicine
Telomeres in Interstitial Lung Disease: The Short and the Long of It
American College of Medical Genetics and Genomics
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Cite this: Genetics of Pulmonary Fibrosis: What Is Known and What's to Come? - Medscape - Oct 23, 2024.
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