As part of working together on a recent EducateNext webinar, I had the privilege of reconnecting with my colleague and mentor, Ellen Macnamara, ScM, CGC. Mrs. Macnamara is a genetic counselor with the National Institutes of Health Undiagnosed Diseases Program.  

Brad: Hi Ellen. We’re excited to host you for a webinar. Can you tell us more about the origin of the Undiagnosed Diseases Program? How did it start?  

Ellen: The Undiagnosed Diseases Program (UDP) began in 2007 as the result of Dr. Stephen Graft and Dr. William Gall’s vision to help the nearly 400 families and patients who had called the National Institutes of Health (NIH) Office of Rare Diseases, requesting help to find a diagnosis. They were moved by the stories these families told about their diagnostic odyssey, but solutions for these patients were a challenge because as a research hospital, the NIH only sees families and participants when they’re enrolled in a study. Studies are traditionally written to either be disease specific or as a screening protocol for an institute that then funnels patients into the most appropriate disease specific study. Without a diagnosis, none of these patients qualified for any existing studies.  

The UDP began as a pilot program with defined goals: to improve the level of diagnosis and care for patients with undiagnosed diseases; to facilitate research into the etiology of undiagnosed diseases; and to create an integrated and collaborative research community to identify improved options for optimal patient management. The program was successful and by 2013 had received enough support to grow into the Undiagnosed Diseases Network. There are now 14 clinical sites across the country, a sequencing core, two model organism screening cores, a data management coordinating center, a bio repository, and a metabolomics core. Since 2013, the UDN has received nearly 7000 applications and evaluated almost 2400 probands. More than 700 people have received diagnoses from their evaluations.  

Brad: I’m imagining that our genetic counseling colleagues might have patients come to mind that could benefit from participating. How are cases referred to you? Are there steps patients need to go through before enrollment?  

Ellen: Patients or their providers must first hear about the Undiagnosed Diseases Network and then apply to participate. Families who are searching for answers might find the program through their doctor or genetic counselor, but also on social media or through support groups. The application requires a referral letter and the submission of the bulk of their medical records.  

After applying, a multidisciplinary team of specialists across the NIH, including pediatric- or adult-specific general practitioners, neurologists, geneticists, etc., reviews the medical records for all applicants and makes recommendations. In addition to determining whether these applicants are appropriate candidates for available research protocols, the team reviews the records and gives recommendations for possible treatment options they may not have explored, even if the candidate isn’t accepted. Only about one fourth of applicants are accepted at the NIH UDP site. Accepted applicants are either seen via telehealth or inpatient admission at the Clinical Center in Bethesda, Maryland. 

Brad: How do you decide which cases to prioritize for participation in the program? 

Ellen: Accepted patients tend to have these things in common: 

• A compelling phenotype. The committee looks for cases that are interesting, but also cases that could respond to available technologies. If there is something new to offer, there is a higher likelihood of finding a diagnosis. 

• Thorough prior evaluation. Every applicant has already had a very thorough prior evaluation from a tertiary care center with multiple specialists. It’s becoming more common for patients to have already had genetic testing, or even genomic sequencing. 

• Favorable family structure.  A favorable family structure might include multiple individuals in the family who are affected or both parents. Having a pedigree that includes multiple family members allows more specific analysis.  

Brad: Once a patient is accepted into the program, what does the experience look like?

Ellen: It starts with clinical evaluation. Clinical evaluation of these individuals aims to document the full phenotype. This is referred to as the “getting to know you” phase. Many patients have already had years of tests. The goal is for the NIH to determine what additional information might be helpful and the best way to acquire that information for any missing pieces of the puzzle. The evaluation is very long and can be exhausting, as the patients is essentially getting a year's worth of evaluations in a week. 

Brad: How does this clinical evaluation differ from what a patient would experience in a typical genetic clinic?  

Ellen: The work that is done at the UDN reflects what the same type of patients may encounter in a general genetics or pediatric clinic, but the UDN is unique in a few aspects of clinical care that they are able to offer.  

• Time. The UDN dedicates time to one to two patients a week.  

• In-depth clinical evaluation of proband and family members as needed. The UDN doesn’t require insurance, which streamlines ordering and performing testing. 

• Research resources: model organisms, metabolomics, data sharing.  

• Ongoing effort to evaluate cases iteratively. The UDN is able to revisit cases as technology evolves and research improves. 

• Collaborations established. 

• Strong participant support and involvement (PEER). Feedback from parents and adult participants helps improve processes. 

Brad: What kind of testing is typically performed as part of the UDP evaluation?  

Ellen: When the UDP started, exome sequencing was the main genetic testing strategy applied. The current approach is to start with genome testing. Research analysis is done in-house and starting with genome allows standardized data for analysis. They also send family SNPChips for CNV and loss of heterozygosity. Proband RNA sequencing has grown from a research strategy to a more routine test done in conjunction with genome sequencing to pair those data sources together. Families receive clinical genome sequencing and they are issued a clinical report.  

Brad: At the end of the UDP evaluation, what are the possible outcomes? 

Ellen: The entire UDP project is focused on identifying a diagnosis for an individual or a family. In about 25-30% of cases, we can find an answer. About half of these are based on results of laboratory testing, and the other half are clinical diagnoses based on their evaluations.  Occasionally, we have VUS identified and additional clinical testing is required to prove that it's a pathogenic variant.  

However, even after their evaluation, most of our cases fall into the category of non-diagnostic results. While our families and us are disappointed to find this, they're also largely quite used to these uninformative results. These cases are prioritized for further agnostic analysis, data sharing, or another route that may lead us to a diagnosis.  

We’ve had cases that were solved after years of waiting. For patients with rare disease, a lot of trial and error remains to find a diagnosis. By having the resources to focus on the patient data and collaborating with other labs and colleagues in the healthcare community, the UDP has been able to provide answers to hundreds of patients.  

Brad: As a genetic counselor working with the families in the UDP, how do you view your role? How do you focus your counseling?  

Ellen: For these families, uncertainty in the face of illness is nothing new, but as genetic information improves, many people look for a genetic cause to explain their condition. It is important to work with families to parse out what it is about a diagnosis that they most want to hear—the prognosis, the treatments, the recurrence risk, the psychological burden. There’s lots of room for genetic counselors to really help families and inspire hope, even in the absence of providing a diagnosis.  

When families are going through a diagnostic odyssey, the striking thing they all share is a feeling of being stuck. It is very hard to be in a place where the patient is having test after test without any answers…and even reaching a point where there are no more tests to pursue. As we mentioned earlier, some patients get results from UDP quickly, but others wait over a decade. As a genetic counselor, it is a privilege to walk beside these families on their diagnostic odysseys, build relationships, and when we can, provide the answers they are searching for.  

Brad: I can see how your role is critical to the program and to the families you serve. Thank you so much for sharing your experience with me.  

Ellen: Thanks for having me. 

To watch the full EducateNext webinar and hear specific case examples where the UDP was able to establish a diagnosis, click here.

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Disclaimer: This blog post is not meant to claim or imply endorsement by the Government of the United States of any work or product of Ambry.