RARE Daily

An Ally for the Undiagnosed Emerges

July 6, 2023

The search for a diagnosis can take many years and requires going from doctor to doctor without finding a definitive answer for people with ultra-rare conditions, atypical presentations, or yet-to-be discovered diseases. A group of undiagnosed and ultra-rare diseases patients and their family members, medical providers, and advocacy partners launched the Undiagnosed Diseases Network Foundation to improve access to diagnosis, research, and care for people with undiagnosed diseases. We spoke to Amy Gray, CEO of the UDNF, about its work, its relationship with the National Institutes of Health-backed Undiagnosed Disease Network, and the organization’s top priorities.

Daniel Levine: Amy, thanks for joining us.

Amy Gray: Thanks for having me, Danny.

Daniel Levine: We’re going to talk about people living with undiagnosed rare diseases, the Undiagnosed Diseases Network, and the Undiagnosed Diseases Network Foundation, which is working to improve access to diagnosis, research, and care in close collaboration with the UDN. Perhaps we can start with the world of the undiagnosed. We hear estimates of the diagnostic odyssey and the patient population. Oftentimes these are based on relatively small studies. What’s known today about how many people are suspected of having an undiagnosed rare disease?

Amy Gray: That’s a great question. I’ll start with rare diseases. Rare diseases are estimated to affect over 30 million people in the U.S. and over 350 million people worldwide, which is roughly one in 10 people, and there are over 10,000 rare diseases. So of these, we know there are a subset of ultra rare diseases, and we know there’s another subset of undiagnosed diseases. However, undiagnosed diseases and ultra rare diseases are more difficult to define, including the overall prevalence. So, as medical research institutions and consortia, such as the Undiagnosed Diseases Network, focus on this area, and as more people undergo extensive genomic characterization, the known incidence of undiagnosed and ultra rare diseases will certainly increase.

Daniel Levine: We also talk about the diagnostic odyssey in terms of averages. In reality, these numbers vary widely. People can be diagnosed at birth or they can go for 30 years or more without an accurate diagnosis. What’s known about the diagnostic odyssey today in terms of time, the number of doctors, and misdiagnoses a patient might go through before coming to an answer?

Amy Gray: Well, for many people with rare diseases, undiagnosed diseases, ultra rare diseases, getting a correct diagnosis can take years, as you mentioned, and many visits to many different doctors. I was speaking with a family just yesterday, and they mentioned that they saw four different doctors just in their state alone before receiving a diagnosis. And that does not even account for the additional doctors that they saw out of state. And this is not an uncommon story. It’s one we hear far too often. Unfortunately, the diagnostic delay for patients really does vary, though. It can be from months to decades, to unfortunately never, and it depends on so many different factors such as the patient’s symptoms, their age, and then of course, access to available resources. You had mentioned averages in some studies, and some of those studies do suggest the average time for a diagnosis of rare disease is about four to five years. And it can be on average close to a decade in other cases. But I think taking a look outside of the numbers, what’s important to know is that during this diagnostic odyssey, people with rare diseases might have so many unnecessary tests and procedures or receive the wrong diagnosis and experienced delays in, unfortunately, getting effective care. And this long timeline, what that can mean for people with undiagnosed and ultra rare diseases, is that their disease progresses and they could potentially miss points in time when interventions could help.

Daniel Levine: Rare disease patients face a lot of difficulties beyond their physical health for undiagnosed patients. These can be even more intensive. Insurance companies may resist paying for treatments for an undiagnosed disease, the uncertainty of what’s ahead in a disease without a name to put on it, and even other questions about their own sanity and veracity when they go to a doctor and are unable to get a diagnosis. What is that burden like for a patient with an undiagnosed condition?

Amy Gray: Well, veracity is a very good word that you used. Unfortunately, most patients living with an undiagnosed or ultra rare disease receive only symptomatic care or symptomatic treatment, if any treatment at all. And an accurate diagnosis, as we know, can result in the better management of the disease or identification of potential therapeutics. And in some cases, patients can avoid unnecessary treatments that do lead to side effects. We just talked about the journey that patients experience towards diagnosis and how it typically does involve multiple interactions with the health system. It can involve inconclusive results and again, in some cases, can include misdiagnosis. So, these challenges for patients not only bring medical challenges, physical as you mentioned, but also mental health burdens for families. And then you couple that, or you add to that the financial and emotional burden on a family. It really does take a lot of veracity for patients and their families. And that’s why having a patient advocacy organization to turn to is so important—so patients and families have the support they need throughout their entire diagnostic journey.

Daniel Levine: We’ve seen a rapid expansion of genome sequencing. The cost of the technology continues to fall, the speed of interpreting the genomes continues to accelerate. New technologies are improving the diagnostic rate. Where are we in terms of seeing this technology used earlier in the diagnostic odyssey?

Amy Gray: Well, it’s estimated that 80 percent of rare diseases, give or take, have a genetic origin. And until 10 years ago, as you alluded to, genetic testing was expensive and the costs are falling. And genetic tests years ago were really limited to a few genes or gene panel at the time. But we’re seeing so many advances now in next generation sequencing, and that has really just created this dramatic effect on the cost coming down, the accuracy improving, and just the utility of genetic testing as a whole. In recent years with these gene panels and then exome sequencing, it has really helped to identify the causes of so many rare and ultra rare and undiagnosed diseases. And these technologies have allowed for the diagnosis of a sizable proportion of undiagnosed patients. Some studies suggest between 25 and 35 percent of undiagnosed patients are being diagnosed and not just diagnosed, but with actionable findings, things that can actually be put into place to help with the treatment. However, and there’s a big however, as fantastic it is that undiagnosed patients are getting a diagnosis, there’s still a large proportion of patients that remain undiagnosed. And so, utilizing these technologies early in the process can help detect findings for, again, roughly 25 to 35 percent of patients. And hopefully with the cost coming down, it’d just be more viable to run these tests earlier in the diagnostic process. And I think what we’re also seeing is programs like the Undiagnosed Diseases Network, and they’ve demonstrated that exome sequencing can not only end that kind of expensive process but potentially the invasive and emotionally challenging journey for patients that helps with the better disease management.

Daniel Levine: I think it still comes as an unwelcome surprise for many patients that pursue genetic testing to find that as often as not it doesn’t provide an answer. But we’ve seen the emergence of things like long read sequencing and RNA sequencing that’s helping improve the hit rate. How well do we understand why we can’t get an answer in many of those cases?

Amy Gray: Well, as you said, technology does hold great promise and not just promise, in some cases actionable findings, but it’s also a numbers game or a matchmaking game. As you see a pattern of certain gene mutations coming up, these scientists can match make them, and the more patients that can get screened, the more data that’s gathered, the better the possibility of matching these causative genes to the shared symptoms patients are experiencing. And that’s why it’s so important that we create as much awareness as we can, and not just awareness, but we increase access and opportunity, especially for those who have been underrepresented and underserved in our healthcare system. Another bottleneck as, as you know, has just been the cost of diagnosis and the cost of these tests in the past and just the time that it takes to investigate these most pressing medical mysteries. Imagine having over 10,000 pages or more of medical records to comb through in addition to looking at the exome sequencing results and trying to determine looking through all of those different medical records what the potential diagnosis can be. That’s very much the case for the participants that go through the UDN. So, there’s time, there’s cost, there’s access. And what we would anticipate with continuous improvements in the accuracy and the affordability of these technologies, but also the utilization of AI to cut down on some of that time that as these advancements take place, it will lead to more promise for delivering those diagnoses that we’re looking for.

Daniel Levine: Do you expect genome sequencing to be used as a newborn screening tool eventually? And if so, what’ll it take to get there?

Amy Gray: That’s a great question. It’s also a very tough question. Of the participants that have gone through the UDN, 50 diseases have been identified, which is pretty remarkable, and as many of those as possible have now been added to newborn screening panels, especially since many of the diseases that we’re talking about affect kids, pediatrics, and they’re very rare genetic conditions that can cause very serious health problems. So, that importance of that newborn screening allows doctors to diagnose babies quickly, and if there is some form of a treatment or therapy to treat babies as soon as possible. And I think we’re already seeing some indications that these technologies are becoming a little more basic as screening tools, but of course, there’s so many different considerations to think about with that, including, you know, ethical considerations.

Daniel Levine: Before we talk about the Undiagnosed Diseases Network Foundation, I thought it would be useful to explain to listeners who may not be familiar with the Undiagnosed Diseases Network to explain what it is, the work it does, and its success to date. Can you walk us through that?

Amy Gray: Sure. The Undiagnosed Diseases Network has just this incredible history and track record. It was launched in 2008 and really established at that time as an intramural research program on undiagnosed diseases to make progress in uncovering understanding and treating rare disorders. And the program’s initial goals were to assist patients with unknown disorders to reach an accurate diagnosis for them and to discover new diseases that provide insight into genetics and human physiology. And there was a lot of success early on. And so, building on the success of the Undiagnosed Diseases Program, the NIH launched the Undiagnosed Diseases Network in 2013 through the Common fund. And at that time, the UDN expanded to include additional clinical sites, a central biorepository, a coordinating center, a sequencing core, a metabolomics core, a model organism screening center, and then expanded again in 2018 to include more clinical sites and a model organism screening center. So today, the UDN has truly been one of the most successful programs, a very robust program funded by the NIH. At its core, it’s a research study with the purpose to bring together clinical and research experts from across the U.S. and to solve the most challenging medical mysteries, really using this highly specialized multidisciplinary approach and these advanced technologies through these cores that I mentioned and through this study, the goal is to help individual patients and families living with these undiagnosed diseases get answers. And the program has been so successful to date, its truly remarkable when you look at some of the numbers. They’ve reviewed over 6,000 applications and evaluated over 2100 participants in this study. And of the 2100 participants that they’ve evaluated, they’ve diagnosed over 650 people, which is a 30 percent diagnosis rate. And again, these are the most complex medical mysteries. And these diagnoses have led to the discovery of 50 new diseases and findings on some of these diseases and the mechanisms of action that are causing them to have led to learnings for other even more common diseases. So, it’s truly been a very successful program, and we look forward to building on that.

Daniel Levine: As you mentioned, the UDN has been funded by the National Institutes of Health’s Common Fund. It was facing statutory sunset of its funding. And my understanding is that the foundation was created in part with an eye toward creating a funding mechanism to support its ongoing work. UDN did manage to secure $18 million in the spending bill that passed at the end of 2022. But what’s the long-term funding outlook for the UDN, and what’s the ongoing need for its work?

Amy Gray: Well, there is a big need for its work. We want to build on the success that it’s had to date. And we are fortunate to have that NH Common funding for 10 years, but it only lasts for 10 years and sunsets after that. And thanks to the advocacy of undiagnosed patients and families, additional funding through the Appropriations Act of 2023 was secured to provide support to the UDN Coordinating Center, the clinical sites and the research course through this September, and then some limited support for the coordinating center and clinical sites through 2028. And it’s really those patients that came together along with other stakeholders in the community because of the dissipating funds from the NIH that felt the need to put this patient led foundation together with the intention to [not only] help grow and sustain and grow the UDN, but to more broadly serve the undiagnosed disease community.

Daniel Levine: What were the discussions around the creation of the foundation and what’s its ongoing relationship with the UDN?

Amy Gray: The discussions around creating the foundation and collaboration with these key stakeholders that came together last summer from within the UDN, I think, really shows the power of the patient voice, the patient community when they gather together and the important collaboration of patients with researchers, scientists, and clinicians. And when you bring those stakeholders together, nothing is impossible. Because the funds were dissipating from the Common fund, there was a need to put some new strategies in place to sustain and expand the UDN, but also to provide this broader support. So, what happened last summer was this group of stakeholders put together a needs assessment and conducted that last summer to better understand what would this funding change mean for the community. And the team identified several opportunities in addition to continuing to support the UDN to help improve outcomes for the entire undiagnosed and ultra rare disease patient community. And really what came out of the conclusion of that needs assessment and those discussions was that there was a need for a new model, a patient led organization that could help moving forward to sustain and grow efforts for the community. And that’s how our foundation was born.

Daniel Levine: You joined UDNF as its inaugural CEO. You have a background in heading patient organizations. Is there something different about heading an undiagnosed disease organization? Are there different challenges you face in working with undiagnosed patients relative to patients who share a common disorder?

Amy Gray: You know, I would say there are similarities in having these different types of organizations, and then there are differences. I’ve learned so much from some of the larger organizations that I’ve worked for. When I say larger, I mean larger size organizations and funding and staffing resources and numbers of patients in the community. At those organizations, you learn a lot about fundraising, best practices, operational efficiencies, strategic program development, and all of these learnings can be applied to more of a startup, rare or ultra rare, or in this case, undiagnosed disease foundation. But also having worked in rare diseases for a number of years, and just recently with the Charcot Marie Tooth Association and other rare disease, rare patient advocacy groups where we did have less funding and a smaller staff size and less resources to work with and a smaller patient community to work with, you find ways to do more with your resources and you take a much more entrepreneurial approach to getting things done and building in all the necessary due diligence and operational best practices, but not letting the red tape or the bureaucracy creep in that you do sometimes see at larger organizations. And really what that means for our organization moving forward is that it’s really important that you know every patient if possible, and every family gets involved in some way. You know, they give their time, their talent. We had a meeting just the other night with this incredible group of volunteers that’s coming together to work with us at the UDNF and they’re working to help us create some patient resources that don’t exist for the undiagnosed disease community. And this group of volunteers, they’re patients, they’re healthcare professionals, they’re all tied to our community, and they have the most incredible professional expertise and personal passion for our mission. And it really ranges from a number of sectors, from mental health counseling to marketing to technology. And so, they’re sharing their talent and their time with us. I guess the point is that everyone can play a role, and we encourage everyone to play a role if they can.

Daniel Levine: In some sense, I imagine people are part of a community that they don’t know exists or may not realize they’re a part of. Is there any surprise in people discovering that the organization even exists?

Amy Gray: Well, we’re doing our best to get the word out about the organization now. Our 501-C3 was just approved this spring. And so, we’re really putting the time and effort into building that community and creating that awareness in as many places as possible. And that’s why opportunities like this one are so helpful to us to really create that awareness within the community.

Daniel Levine: As you think about people living with an undiagnosed rare disease, what’s the greatest needs they face?

Amy Gray: That’s a tough question. I mean, there are so many needs that the undiagnosed and ultra rare disease community faces. They’re looking for answers throughout the diagnostic journey. They’re looking for access to research, to medical care and support. And I think one of the biggest needs that they’re looking for is they’re looking for a community that they can turn to other patients and other families of a support system, so to speak. And diagnosis is just one of the unmet needs faced by the community. But when a patient receives a diagnosis, then they most likely will not have an available therapeutic option. And so, this underlines the need for follow-up research and development, looking at genetic therapies and repurposing existing drugs. But we also know there’s challenges like access to diagnostics, access to research and care and therapeutics, and that they don’t equally impact all members of our community. We know that communities of color disproportionately experience the burden of rare disease. And even at the microcosm of the UDN, we see how patients of color, low income, and geographically isolated patients and families, and also those with limited English proficiency face barriers to equitable access and resources and processes. So, that’s something that we need to work on and that’s why our foundation is led by patients and families and really hopes to become that central resource to help provide the resources for those unmet needs that the communities are looking for from us. And we truly believe that no patients or families should have to go through this journey alone.

Daniel Levine: Does the organization expect to work on the policy front at all?

Amy Gray: You know, when we did the needs assessment last summer, it was really evident to the team involved that there are some great organizations already focused on advocacy in the rare disease space. So, I would say, it’s not a core pillar of our mission. However, we do intend to support those advocacy organizations and those advocacy efforts and be involved in those policy discussions, especially when it comes to topics like appropriation funding for the UDN, genetic testing, access to treatments, and some of those other unmet needs that we just discussed. So, we really truly envision our role is to be a partner with those advocacy organizations, but also to encourage the patient and community to get involved both at the state and federal level.

Daniel Levine: As you think about the organization’s work, what are the top priorities initially?

Amy Gray: Well, our priorities really revolve around improving access to diagnosis, to research and care for the community. And there’s kind of four key areas that we’re going to be focused on initially. The first is the sustainability and growth of the work within the UDN. We are going to do everything in our power, in partnering with other advocacy organizations in the patient community, to ensure that the UDN has the appropriations funding moving forward. And of course, the foundation will be kicking off our own fundraising efforts to not only sustain, but expand the work of what’s going on within the UDN. The second key area is around this area of patient and family navigation and we’ll be launching a program called a Patient Navigator program, and really the intention of that is to help guide patients and families throughout the diagnostic and therapeutic odyssey. So, we’ll be focused on helping improve access to diagnosis, access to treatments, improving their experience going through the diagnostic odyssey. And hopefully all of that will lead to better outcomes for patients. A third really important area, and one of our core mission pillars is this idea of community outreach and building a community for the undiagnosed and ultra rare disease community. You know, we hear from so many families, especially those that are undiagnosed, that they just don’t feel like they have a home to turn to or a place to turn to, and we want to build that community for them and for their families. And then also a really important thing that we’re working on is developing strategies in collaboration with the UDN and other patient advocacy groups to improve access and health equity and to remove some of those barriers that exist. And then I would say the fourth and final key area that we’re working on and focused on initially is patient-centered research and clinical care. Our ultimate goal is to create what we call a learning healthcare network. Initially we really want to start out by looking at the patient experience and how we can optimize that, and then also look at standards of care and what those standards of care are, and how they can be shared more broadly across the healthcare network and the healthcare system. So, we have a lot of work ahead of us. We’re excited to embark on this work. We have an incredibly dedicated board of directors, strong collaboration with the UDN and NIH leadership and with other patient advocacy groups and developing collaborations with them. We really look forward to building a community of resources for the undiagnosed and ultra rare disease patients and their families.

Daniel Levine: Amy Gray, CEO of the Undiagnosed Diseases Network Foundation. Amy, thanks so much for your time today.

Amy Gray: Thank you.

This transcript has been edited for clarity and readability.


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