CPF Spotlight l Undiagnosed Diseases Program with Dr. Thomas Cassini

What happens when patients go years without a diagnosis despite countless appointments, tests, and referrals?

In this episode of Cumberland Conversations, we sit down with Dr. Thomas Cassini, Pediatrician and Geneticist, with Vanderbilt’s Undiagnosed Diseases Program at the Potocsnak Center for Undiagnosed and Rare Disorders. We explore the important work of the Undiagnosed Diseases Center and the impact it has on patients and families searching for answers. Our conversation dives into the challenges of identifying rare and complex conditions, the value of multidisciplinary collaboration, and how the expansion of the program is allowing more patients to be seen and diagnosed.

Want to learn more about the program or refer a patient? Visit vumc.org/undiagnosed to learn more.

Transcript

SPEAKER_01 0:00

Hey there. Welcome to Cumberland Conversations. This is the place where we talk about the issues that matter most to you, your patients, and your community. We're diving into real conversations with real people, sharing insights you can actually use. Let's get the conversation started. Hey everybody, it's Rob Lillard, Medical Director of the Cumberland Pediatric Foundation, welcoming you to another episode of Cumberland Conversations, our podcast about what's going on in the medical community around Tennessee. One of the things we like to do is spotlight some of our members, be it in primary care or in specialty work, and highlight what they do to improve the health care of Tennesseans. And so I'm happy to be joined today by Dr. Thomas Cassini with the Vanderbilt University Undiagnosed Disease Program. So, Dr. Cassini, welcome. Glad you could join us today. Thank you. Let's start by telling if you could tell us a little bit about yourself and your background and how you ended up here in Nashville.

SPEAKER_02 0:52

Of course. Yeah. Well, um I just wanted to start out by saying thank you and the Cumberland Pediat Foundation for having me and uh always appreciate the opportunity to talk about the program here. So uh myself, I am a uh pediatrician internist and geneticist by training. Uh I actually grew up in Wisconsin and did my uh early education and medical school training up there at the University of Wisconsin. Was looking for a little warmer environment for residency, which is part of the reason I ended up down here in Nashville. Obviously, Vanderbilt was the main reason, but uh the weather was a nice side benefit there. So I did uh combined internal medicine pediatrics residency here at Vanderbilt and then a chief resident here on the medicine scientist here uh for five years before heading out to the East Coast to do my genetics training, where I did a clinical and biochemical genetics fellowship out there. Uh, and then came back for a faculty position at Vanderbilt here, where uh I started as the associate director for the Center for Undiagnosed Disease here at the Vanderbilt Undiagnosed Diseases program. I joined uh Rizwan Hamid, who's the director of the center and the program leadership, and have served in that position since.

SPEAKER_01 1:53

Yeah. Well, you you came back and took it by the horns, and so that's awesome. Uh so obviously it it sounds like an impressive program. Tell us a little bit more about how it's structured, because I think you were explaining to me actually several different things kind of rolled into one.

SPEAKER_02 2:08

Yeah, absolutely. So the Vanderbilt Undiagnosed Disease Program is uh sort of the umbrella uh term for the center. It actually began as the Undiagnosed Diseases Network site back in 2014, uh, which is the NIH-funded clinical research consortium uh that began at the NIH intramurally in 2008 and then expanded out to six new centers across the country in 2014. That's where Vanderbilt became involved. And so this program has the dual goal of providing answers for patients and families for medical mysteries that have long eluded diagnosis via typical means, uh, and then also furthering medical science in the process with research and learning from these rare disease presentations. Now, the Undiagnosed Disease Network, while successful, uh served a relatively small number of participants each year. In the beginning, it was about 15% per year and expanded out to about 30% per year in the second phase of the program. But obviously, you know, with six to then 12 centers in the second phase, there's many more patients that need that type of evaluation than the catchment area of each of those centers. And so that's where fortunately Dr. Balzer and the rest of the uh Vanderbilt leadership saw the need for this uh growing patient population uh and started um uh with a generous contribution from the POTU-Snack family, the POTUSNAC Center for Undiagnosed and Rare Disorders. So that's the clinical program that's internal to Vanderbilt here, where we seek to take what we've learned through the undiagnosed disease network and then expand that out at scale. And so, you know, where we're still limited by the NIH funding to you know 30 to maybe 50 patients a year that we can see through the undiagnosed disease network, we now have this additional program. And our goal is to grow out over the next five years to be able to see a thousand patients per year.

SPEAKER_01 3:54

Every year. Yep. So from 15 to 1,000.

SPEAKER_02 3:57

Yep. Okay. So we're making progress along.

SPEAKER_01 3:58

We managed pretty quick. Yep, that's yeah, that's a pretty good growth rate.

SPEAKER_02 4:01

It is, yeah. I've spent a lot of time on the on the back of an envelope on how this should should look over the next few years. So uh we saw uh 138 patients in calendar year 2025. Okay. Um, and we're continuing to grow in our referral volume. We're, you know, over the the course of uh calendar year 26 years, we're getting about one referral a day. Um and so we are doing our best to you know see and evaluate as many as we can and try to find answers for those who's amazing.

SPEAKER_01 4:32

So tell me a little bit about, you know, I think you were telling me earlier that it's about a two-to-one ratio of adults to children come to the clinic. But and obviously a lot of viewers here are going to be, you know, concentrating on pediatric care. But if you have some family practice and other uh folks in our foundation that might see adults, walk us through a little bit about what patients are ideal for those referrals, because especially for in a pediatric realm, I can think of when I was in practice, um, you know, you might for hypotonia, you might refer to neurology or a single specialty. So, what what would make you identify a patient as a good candidate for this clinic?

SPEAKER_02 5:08

Yeah, that's a great question. Um, and and you kind of alluded to this, you know, we didn't want to limit ourselves to just adult patients or pediatric patients. Um, we also didn't want to limit ourselves to just genetic concerns, which is the main focus and has been the main focus in the undiagnosed disease network, although we do try to make other diagnoses through that. Um but within the Vanderbilt Undiagnosed Diseases program across the entire center, we now have uh 11 physicians that cover 16 different specialties and subspecialties. And so we do have a wide and growing array of expertise there. Really, it's anybody who has uh gone as far as they can along the diagnostic uh algorithm and has not reached a diagnosis. So, really, the only two eligibility guidelines that we have for the program are uh the patient has some objective finding of their disease, laboratory marker imaging finding, um, and they don't have a diagnosis that explains that objective finding. Uh and so if anybody in their care feels like that we can be helpful and they meet those criteria, we're happy to get them in and see them. And there's various ways that we aim to help people from even just record reviews all the way up to you know multidisciplinary clinic visits with research um uh building off of their and you said an objective finding.

SPEAKER_01 6:27

Do you mean like a physical finding, like say hypotony, or do you want something abnormal on a specific?

SPEAKER_02 6:32

No, it could be a physical exam finding too. Yeah, yeah. Um you know, we just have found that over time that uh patients with symptoms, but no, you know, objective exam correlate or laboratory finding, unfortunately, have a very low probability of being diagnosed through a program like this. And so while there's been a tremendous investment uh by Vanderbolt on the program, we still have to be mindful of the resources and try to help the undiagnosed community as a whole as best we can. And so we really try to target it to those who we think we have the highest chance of finding an answer for.

SPEAKER_01 7:04

So what does that process look like? If you in your practice identify a patient that you think might be a good referral, who's the contact? How does it work? What's the process of getting in?

SPEAKER_02 7:14

Yeah, so we want to make it as easy as possible to get people into the program. So we have a website, vumc.org slash undiagnosed. And if you navigate to that website, there's a radio button up in the upper right corner to refer a patient. That'll take you to a link for a red cap. It takes maybe about 10 or 15 minutes to fill out, uh, and that will get the ball rolling for our team to kind of take over from there. So we'll we'll um send a red cap to the family to fill out, reach out to them to answer any questions that they may have along that process. And if they're interested in continuing forward and our team feels like, you know, the they would be a good fit for the program, um, we would then bring them into our clinic. So we now have our own dedicated clinic space out at 100 Oaks, where uh we have different multidisciplinary specialty clinics. You know, one week it might be um genetics and rheumatology and immunology, and then the next week it might be uh genetics and pediatric neurology and complex care. And so fit those in like depending on the presentation, you pick a day where that's try to get nice as best we can so that the evaluation all gets done in one morning. So the patient will come in and sit in the same room, uh, and different specialists will go in and out and and see them. We'll all kind of meet afterwards and discuss our thoughts, go back in and share them with the patient and decide on where to go from there for additional testing, or if we think we might be able to make a diagnosis based on what's been done already. So it's uh it's a lot of fun, actually. It's right sort of what I've I was hoping medicine was going to be like when I wanted to be a doctor, where you know it's other doctors sitting around talking, thinking about challenging cases, and now you know I really get to do that. So it's a pleasure to be a part of a program like this.

SPEAKER_01 8:49

Well, that's awesome. So I'm and you assume that if they've gotten to this point, they've been through testing, genetic testing, and things like that. Is there ever a process where you might prior to the appointment go back to the referring physician and say, can you order this ahead of time?

SPEAKER_02 9:02

Yeah, that's exactly right. And so that's one of the things that over time we've tried to do a little bit more of, right? There's limited spots for how many people can come in and see a number of specialists, but as we grow to a thousand, not everybody is going to come in and see four different subspecialists in their evaluation, right? And so what we've started to do is build out different tiers of evaluation to meet people where their diagnostic needs are at. And so one of those might just be a record review and say, yeah, we recommend these tests, or based on our record review, you know, we think they have this diagnosis based on these constellation of findings and they should continue with their uh longitudinal providers for treatment. It might just be that they need to see a single provider to kind of solidify a diagnosis too. And so um, we're also looking to build out a lot of our telemedicine capabilities to increase our reach across Tennessee and around the region too for visits like that, where you know, we think um a diagnosis may be apparent from the records, or we want to see if the patient may be a good fit for coming in, uh, but don't want to make them necessarily travel for several hours to do so, yeah, exactly. Um, and so as we go, you know, to try to make um both the program resources go as far as they can, as well as, you know, meet patients where they're at for what they need, uh, we want to make sure that we have different options available.

SPEAKER_01 10:16

And we have several members who might be watching this are you know in remote areas of Tennessee or a little further away from nationals. Is that something that's active now, or is that in the planning stage?

SPEAKER_02 10:24

Within Tennessee, yes, we can do uh telemedicine visits now. Typically we've done those for genetics, rheumatology, and and neurol, uh although um, you know, like I said, we're we're looking to build that out, but it is currently an option available. Yep.

SPEAKER_01 10:38

Okay.

unknown 10:38

Right.

SPEAKER_02 10:39

So a family in Johnson City could follow that process and get hooked up and and if we think that telemedicine would be a good start, we can do that. Sometimes, obviously, we we think they may need to come in and see us in person so we can talk the family through that. But certainly anybody across the state should feel like they have access to our program.

SPEAKER_01 10:58

Now you mentioned some of this is NIH supported, obviously. So we always have to ask, tell me about insurance coverage. Do families sometimes find roadblocks or getting into the clinic due to that, or where do we stand with that?

SPEAKER_02 11:10

Uh it can be um something that we have to work through. Yes, I'll say I'll say it that way. All right. So we do have the NIH program that's still active. Um it has a more limited number of slots available each year, but for families who may not um, you know, have insurance where they could be seen at Vanderbilt or for whom there's other, you know, logistical limitations for why they couldn't come into our clinical program. Uh, if they're eligible for the the research-based program through the NIH funding, um, we can certainly get them in or encourage their providers to refer them in through that program. Um like you mentioned, that program is all NIH funded, so there is no cost to the patient for participation in that program. Whereas the clinical program does build through typical insurance coverage and and uh like any other doctors would operate now.

SPEAKER_01 12:01

Okay. Tell me about the communication back to the primary care, back to the referring provider.

SPEAKER_02 12:06

Yeah.

SPEAKER_01 12:07

Um, what what's the typical time frame and how does that work? Yeah.

SPEAKER_02 12:12

We want there to be an open line of communication as much as possible. And so we will send a letter after our initial review about the um the patient referral, um, either letting them know any recommendations that we have. If we don't feel like the patient necessarily needs to come in for the visit, then they'll send that letter back. It has our contact information in there. People are more than encouraged to reach out with questions or um if they have different thoughts than us, we're always happy to pick up the phone and have that conversation, set up a meeting, um, whatever we want. This to be a fluid back and forth process. After they've come in and seen us, we'll also then prepare a summary document afterwards that has all the notes from the providers that they've seen, as well as a synopsis of kind of our overall program thoughts and a list of diagnoses and recommendations if we're able to make those.

SPEAKER_01 12:58

Okay. And do most patients come in for just a singular visit, or is there a follow-up uh plan that is generally part of that? Or does it vary, I guess?

SPEAKER_02 13:08

It does vary, yeah. So the goal is, you know, to to make this as little burden on patients and families as possible. And so ideally, we'd love to get it done in one visit. Okay. Obviously, that's not always possible. Um one of the really nice resources that we've been able to build down is a tremendous support team as well. And so if we need to organize follow-ups, it may be that um they're able to get in and see a nurse practitioner, which has a little more flexibility in the scheduling there to just kind of get some updates, share our updates on behalf of the program and talk about the next steps and where we think we should go from here. Sometimes we do have to bring people back in for a second multidisciplinary visit as well. That's a little less less common now that we have more specialties involved and have sort of uh planned out our clinic days well. But yeah, that still does happen sometimes where where people have to come all the way back in for a second visit. But we try to minimize the back and forth that much as we can.

SPEAKER_01 14:00

What have they ever stumped you? Have you ever yeah, so sometimes the undiagnosed remain undiagnosed.

SPEAKER_02 14:07

Yeah. Okay. As much as I would love to say we can guarantee that you'll get a diagnosis out of participation in the program. That's that's not realistic, unfortunately. Uh, there are um people for whom we can't reach a diagnosis still, despite all of our best, you know, multidisciplinary clinical and research efforts in up in the program. You know, we will do the best we can to share our thoughts and recommendations of what you know we think we should do from here. Some people will might remain with their case open and sort of an inactive state in the program. You know, we know as a geneticist, they uh have the most familiarity with you know reanalysis of genome sequencing over time and how we learn new things about the human genome over time. Patients' presentations change over time. And so we know there's good data for genome sequencing that looking back at that one, two longer years later, sometimes we can make diagnoses that we couldn't the first time around. And so just because you aren't diagnosed after your initial visit or those labs that that come back or within the few months after that, um, doesn't mean we we might not be able to reach a diagnosis for you down the road.

SPEAKER_01 15:11

I'm gonna flip that around and I'm gonna ask you what's your most exciting or rewarding experience you've had so far where somebody's come in and you've really uh uncovered something?

SPEAKER_02 15:21

Yeah, um that's a great question too. It's uh um you know, this is a really typ not a typical case, but uh an exciting case that sort of showcases a lot of the the resources and dedication that we have in the program, and I think highlights how you know I think what a lot of people are familiar with, or you come to us to get your genome sequenced, hopefully we get an answer or we do research off of that. But we're looking to diagnose non-genetic cases too. And so one patient was referred to us for developmental delays, sensory neural hearing loss, and some brain malformations on their MRI that had remained undiagnosed. We saw them for a genetics clinic visit. We didn't reach a diagnosis through genome sequencing. At that point, we went back and reviewed the MRI sequences with uh Dr. Puthi, one of our neuroradiologists here, who has a lot of expertise, and he looked at it and was like, I don't know why this case is puzzling. This patient has congenital CMV. Um, we were like, okay, well, that's interesting. Um, how do we go about proving that? And so uh we collaborated with our infectious disease specialist here, Dr. Buddy Creech. Yeah, is it good one? Yep, who recommended uh that, you know, it's possible if we had a blood sample from around the time the patient was born to get a CMV PCR done on a research basis. He had a research contact who was able to do that. And so one of our nurse practitioners in the program, Kim Mizel, worked with the patient's mother to go back and get the newborn screening blood spot card from when the patient was born in Virginia. Uh, got that shipped to the researcher. They ran the CMV PCR and it came back possibly. That's amazing. Yeah, all right. Uh so we were able to make a diagnosis for that family and give them some good prognostic information, plug them in with the right set of specialists and get them um on their way with the diagnosis to move forward.

SPEAKER_01 17:12

Oh, that's really cool stuff. So anything else that you feel like uh the Vanderbilt family or anybody listening needs needs to know uh about the clinic that we haven't talked about already?

SPEAKER_02 17:22

Yeah, and I guess we we haven't really talked much about the research arm of the program as well. And so um, you know, one of our hallmarks, and I think one of the ways that we're able to really be successful in making diagnoses is through that collaborative research. We talk about a lot of the collaborative clinical side of things, but there's a similar process on the research arm too. So it's best fleshed out for the genetic side of things where if somebody gets genome sequencing that's non-diagnostic, uh, we'll get that raw data and reanalyze it ourselves and we'll share that with several different research groups around the medical center. Uh, and then we'll all come together and meet for what we call our genome data board, or we'll um go through kind of the clinical expertise on the case and then uh see what our research algorithms have have turned up for this and decide where to go from there. And so we we make a lot of diagnoses at at that meeting as well for things that were just not um picked up through typical clinical sequencing. Um so that's a really exciting part of the program. So I guess you know the take-home message is reach out to us about any undiagnosed patient that you think we can be helpful for, or even have questions about whether we can be helpful for. Um not being able to get a certain test shouldn't be a barrier, distance shouldn't be a barrier. We'll we'll find ways to to work through it and try to get people answers. And that may take, you know, a week at the clinic visit, or it may take years, but keep working at it.

SPEAKER_01 18:44

Well, that's great because one of the things that we really talk about a lot is maintaining access to care and trying to meet people where they are, not putting up barriers to care. So a lot of things that you're doing are really exciting to expand that access to people who are really struggling the most, it sounds like.

SPEAKER_02 18:58

Absolutely. You know, when you only had 15 slots a year, they had to be kind of allocated to people who had had all the MRIs, all of the sequencing, the really million-dollar workup. And that's their goal in building out this program is that it's not limited to that population anymore. That whatever step they're at in their diagnostic uh workup, if anybody thinks we can be helpful, we want to take a look and and see how we can help.

SPEAKER_01 19:21

Well, good. Well, we are glad that you found your way back to Nashville to to kind of anchor this program. And we appreciate you coming in and talking about it today. And uh, you know, certainly people can reach out to us if they have any questions uh about it. We can direct you to the right uh resources or the website again is through Yep.

SPEAKER_02 19:38

VUMC.org slash undiagnosed.

SPEAKER_01 19:41

Perfect. And that's where they can find the referral.

SPEAKER_02 19:43

That's right. And more information on the program if you're interested in reading a little bit further.

SPEAKER_01 19:47

Awesome. Well, great. Well, again, this is a great way that we like to spotlight a lot of our members and things that are going on in our community. So if you have something you want to hear about, please reach out to us, cpfnashville at gmail.com. Uh, we'd be happy to hear from you and let you know what you want to hear about. So thanks for joining us and we'll see you next time.

SPEAKER_00 20:06

Thank you for joining Cumberland Conversation. We're proud to support the people who care for Tennessee's children. Don't forget to subscribe so you never miss an episode and stay connected with CPF for more tools, trainings, and community updates. Until next time, take care.