Finding a Path Through the Land of the Undiagnosed

By Alissa Kocer


We visit the doctor when we aren’t feeling well to help us figure out what’s causing our symptoms and design a treatment plan. Sore throat? Take a throat swab to check for strep throat. Chest tightness? Listen to the lungs and run breathing tests to check for asthma. A lump? Biopsy it to check for cancer.  

Some 30 million Americans, though, experience significant health problems that defy diagnosis. Their symptoms range from mysterious heart attacks in teenagers to spine abnormalities, intellectual disabilities, low muscle mass, digestive troubles, and countless others. Their ailments don’t follow well-known disease patterns. 

In many such cases, doctors order batteries of tests: DNA sequencing tests to gather information about genetic changes that may cause disease, exome sequencing tests to examine the protein coding regions of the genes, and imaging scans like MRIs, PET scans and CAT scans to get a detailed look inside the body. 

But even then, diagnoses elude these patients. At a loss, they seek answers on the internet or in medical books. Perhaps most desperate are the parents of children suffering from mysterious maladies. “As I sit to summarize [my daughter’s health history], I find myself tearing up and very emotional,” said one parent, as documented in a personal narrative. “Nine years of chronic medical crisis and so many failed treatments leave so much to recap.” 

What are patients and parents to do when every medical journey they take leads to dead ends and unanswered questions?

Vandana Shashi, MD, is helping pave the way to more answers. As a clinical geneticist for 25 years, she is well-versed in the worries and frustrations that come with undiagnosed, rare, and ultra-rare diseases. 

“Geneticists have been living in the land of the undiagnosed for a very long time,” said Shashi, a professor of pediatrics at Duke University School of Medicine. “Probably half of our patients have been undiagnosed for years, decades even.” 

Shashi is a principal investigator in the Undiagnosed Diseases Network (UDN), which works to help patients get diagnoses and advance our understanding of health and disease. Duke is one of 12 clinical sites across the country that constitute the UDN, along with a coordinating center and three core facilities. The UDN, which was established in 2014, is funded through the National Institutes of Health (NIH) until 2023. After that, new sources of funding will be required to continue the work.

Shashi oversees efforts at the Duke clinical site. To date, she and her colleagues at Duke have achieved the largest number and highest rate of diagnoses of any site across the UDN. They also have discovered the largest number of new disease genes in the network.

An Avenue of Hope

Patients with undiagnosed diseases exhibit a spectrum of symptoms. About 60% experience neurological disorders ranging from unexplained seizures and tremors to rapid cognitive decline that can leave a once healthy child unable to crawl, talk, or even recognize sounds. 

“The nervous system is extremely sensitive to these genetic aberrations or mutations that can occur in really important genes that are crucial for how the neurons function,” Shashi said.

Other patients might experience severe constipation, acid reflux, arm weakness, vision problems, involuntary muscle contractions, inflammatory skin lesions, or even slip into a coma for no apparent reason. 

And while these diseases vary widely from person to person, one thing unites them: a lack of answers or a path forward.

The UDN provides an avenue of hope. Difficult-to-diagnose patients typically reach the UDN through referrals from their primary care physicians. Patients or their parents complete a short online application that is reviewed by the UDN Coordinating Center at Harvard University. The Coordinating Center determines which patients to accept and which site to send them to. To date, the UDN has received 5,700 applications and accepted 2,246. “For those who are not accepted, we still try to provide a specific recommendation to help them,” Shashi said.

For those accepted into the program, the team carefully combs through each patient’s medical records and reviews all previous clinical notes, images, and test results. 

“Most patients have already had genomic testing before,” Shashi said, “so we can reinterpret those data with our bioinformatics pipeline and search for likely pathogenic variants.” 

As science evolves, genes and variants can get reclassified and reinterpreted; sometimes one that initially raised no red flags ultimately becomes a variant of interest. “We are not saying that something was missed along the way by other clinicians,” Shashi said, “only that science has evolved, and researchers have gathered more information about genes and variants.” 

'We Don't Give Up' 

For about 4% of patients, a diagnosis is possible after the initial medical review. The rest move on to a second phase of testing and data collection. Duke UDN patients come to Duke Health for a comprehensive evaluation. The UDN pays for their travel and genome sequencing expenses. The Duke clinical site is one of the few sites that also covers all patient costs, including clinical evaluations, labs, procedures, and imaging. “We absorb all of the costs as part of our site to minimize the burden,” Shashi said. “This way, our patients don’t have to negotiate with insurance companies.” 

Sequencing data are generated by the sequencing core at Baylor University for initial analysis. Once completed, the raw data are sent back to Duke to reanalyze in a process that takes 4-6 months. 

Typically, clinical labs and research studies use a filtering process to try to match sequencing data with a patient’s symptoms. For example, if a patient has tremors, researchers may analyze the sequencing data specifically to search for genes known to be implicated in tremors. This filtering, though, can cause potentially relevant genes to be missed: a potentially causal variant may be “filtered out” because it isn’t already known to be associated with the patient’s clinical features. So the scientists at the Duke UDN site analyze data without filtering for specific symptoms.  

“When we reanalyze the raw data at the Duke UDN site,” Shashi said, “We don’t look at the phenotype. We just look for data that seem compelling.” Analyzing data without filtering for symptoms is both innovative and laborious, but it has provided results. The Duke team has been able to either make a diagnosis or find a strong lead in 40% of its cases. The network-wide rate is 29%.

Once the data have been analyzed and reanalyzed, providers meet with patients to discuss their results and conclusions, which are also sent to the patients’ primary care providers. While many patients receive a diagnosis through the Duke UDN’s analysis, approximately 60% don’t. But Shashi said, “No case is ever closed. We don’t give up.” 

What's in a name?

headshot of woman
Allyn McConkie-Rosell, PhD

UDN clinicians, virtually by definition, diagnose rare diseases. Some patients are the first ever to be diagnosed with a newly identified disease. Existing information or treatment protocols for these diseases tends to be sparse to nonexistent. 

But still, diagnoses matter. 

“People search for a diagnosis,” said genetic counselor Allyn McConkie-Rosell, PhD, a professor in the Department of Pediatrics and a UDN social scientist, “not because they need a name, but because they need help.” 

A diagnosis can provide much-needed clarity and help patients and their families end the seemingly interminable search. “I’ve had parents say they had slept for the first time in years once they got a diagnosis,” Shashi said.

About 25% of patients who receive a diagnosis undergo a change in their medical management, such as medications or additional screening for issues like heart muscle disease or cancer predispositions. 

But every patient — even those with no change in treatment — benefits from having a diagnosis. 

Parents worried that their child’s disease might be heritable can get guidance about the risks of having another child. The steep financial and emotional costs of searching for answers — repeated imaging, visits to specialists, endless testing — are eliminated. Once doctors know what they’re dealing with, they can focus on ways to help treat the disease. 

For those patients who don’t get a diagnosis, they at least have a little peace of mind knowing they have done everything science currently offers. “The limitation is what we don’t know yet,” Shashi said. “And families appreciate that we aren’t leaving any stone unturned.”

Feeling Heard

Under Shashi’s leadership, the Duke UDN clinical site has led or contributed to 18 new gene-disease associations and is currently pursuing another 25.

In addition to the raw science they uncover, they are also gaining insight into the human toll of living with an undiagnosed disease. “We want to understand what these families go through,” Shashi said, “and what they expect from the information we are able to provide them with. What does getting the diagnosis mean versus not having one?”

The Duke UDN clinical team gauges how well parents cope with their child’s diagnostic odyssey via questionnaires that assess anxiety, depression coping strategies, and health care empowerment. Duke was the first site in the network to ask applicants for a personal narrative of their illness journey, which gives patients a chance to tell their stories in their own words. This practice has now been adopted across the network.

These narratives give the UDN team an inside look at how families deal with the stress of being undiagnosed. Many patients appreciate the opportunity to share their stories and feel heard. 

“I can’t explain the fear and rush of emotions we felt as parents knowing nothing about seizures or epilepsy at that time,” said one parent. “We truly thought we were losing him.” 

Some parents write about the strength and resiliency of their undiagnosed children: “As parents, we want nothing more in the world to figure out what is going on with her,” wrote one. “She has determination that is mind-blowing; she is our hero.” 

There is still a lot of uncharted territory to map and more work to do to create paths of hope for people in search of a diagnosis, but Shashi is emphatic about one thing: “We will not leave these families behind.”

Alissa Kocer is the communications strategist for the Duke Precision Genomics Collaboratory.

Photos and video by Jim Rogalski, senior multimedia and video producer in the School of Medicine's Office of Strategic Communications.