As part of an ongoing effort at Yale School of Medicine (YSM) to better understand rare diseases, a team spanning multiple departments and specialties from YSM and Yale New Haven Hospital has received a grant of approximately $3.35 million from the National Institutes of Health (NIH) to join the Undiagnosed Diseases Network as a new Diagnostic Center of Excellence. The Yale Diagnostic Center of Excellence (YDCoE) will partner with key stakeholders in the community to increase genetic testing and diagnostic efforts in the Yale New Haven Health System and other health care systems in the state of Connecticut for patients with unexplained or undiagnosed symptoms, especially those from underserved groups.
An estimated 300 million people worldwide are living with rare diseases, many of which are so uncommon that they may be entirely new to medicine and remain undiagnosed by clinicians for many years. These diseases, which are often genetic in origin, can cause severe physical and mental impairments that shorten lifespan and diminish quality of life. In the United States, rare diseases are defined as affecting fewer than 200,000 patients, according to the 1983 Orphan Drug Act.
Rare diseases vary widely in their causes and symptoms. While some have characteristic features — for example, the “café-au-lait” spots that appear commonly on children with neurofibromatosis type 1—other rare diseases can be more difficult to identify. Many rare diseases often involve unexplained symptoms that don’t fit the criteria for more typical diagnoses.
“The challenge is there are so many diseases we have not even made a diagnosis for,” says Yong-Hui Jiang, MD, PhD, professor and chief of medical genetics at YSM and principal investigator of the new center. “In medicine, if you don’t know what a patient has, it’s very challenging to figure out how you can help them.”
There are 7,000 known rare diseases, but only about 5% of those have treatments approved by the Food and Drug Administration. For many patients, especially those who are undiagnosed, treatment may be limited to symptom management. But if a diagnosis is made, physicians may be able to provide more targeted therapies—including new genetic therapies where appropriate—while avoiding unnecessary treatments.
The Undiagnosed Diseases Network (UDN) was established in 2013 by the NIH Common Fund with the goal of connecting research and clinical sites across the United States in order to better understand and treat patients with undiagnosed diseases. Undiagnosed diseases are defined as long-standing symptoms or elusive medical conditions that have not been diagnosed despite extensive clinical evaluation. Undiagnosed diseases are often connected with rare conditions. The UDN has just entered its third phase in which over 20 clinical sites, now including Yale, will apply their rare disease research with a particular focus on expanding access to underserved patient populations.
“We are excited to become a phase III new site for the UDN. It’s a significant honor for the community and for the hospital to be recognized for our many years of expertise based on our work on rare and undiagnosed diseases,” Jiang says.
Using genetic testing to diagnose rare and undiagnosed diseases in underserved populations
Yale offers a number of innovative genetic diagnostic methods for rare diseases, and one of the primary goals of the new center will be to expand availability of these resources for groups of people who have historically faced barriers to accessing them.
“Over the past 15 years, the advance in technology is unprecedented and has offered a lot of opportunities to figure out new diagnoses,” says Jiang. “Unfortunately, that benefit is unequal. Uninsured and minority populations have not benefitted to the same degree as populations with greater resources, so we want to focus on these underserved individuals with this grant.”
Over the past 15 years, the advance in technology is unprecedented and has offered a lot of opportunities to figure out new diagnoses.
Yong-Hui Jiang, MD, PhD
Jiang and his team of investigators will work with community-based organizations to enroll patients experiencing unexplained or undiagnosed symptoms. One major partner is Fair Haven Community Health Care, a federally qualified health center located in the greater New Haven area. FHCHC cares for approximately 35,000 unique patients each year, the vast majority of whom identify as being from racial and ethnic minority groups.
“We at Fair Haven Community Health Care are thrilled to partner with this team. The work clearly aligns with our mission to bring the highest quality of care — the best of what modern medicine has to offer — to some of Greater New Haven’s most minoritized populations,” says Benjamin Oldfield, MD, assistant clinical professor of internal medicine at YSM and vice president of clinical affairs at FHCHC.
The YDCoE will also partner with Project Access New Haven to provide patient navigation services, as well as with Transitions Clinical Network, led by Emily Wang, MD, MAS, professor of medicine (general medicine) at YSM and of public health (social and behavioral sciences) at the Yale School of Public Health, to enroll formerly incarcerated patients, a population that Jiang says typically does not have easy access to diagnostic genetic services.
“It’s almost like a forgotten population,” he says. “You cannot say they don’t have genetic problems. They do.”
One goal of the YDCoE will be to perform educational outreach efforts to primary care physicians at FHCHC to help them incorporate genetic screening into their practice. By educating physicians on some of the most likely rare diseases to watch for, physicians might be able to diagnose and treat certain diseases earlier.
Diagnosing and researching rare and undiagnosed diseases
Over the next four years, the center will take a multi-tiered approach to diagnose and research suspected rare diseases in the patients they recruit. Tier 1 will involve reviewing a patient’s medical record to see if it suggests that the patient has a rare disease. If no diagnosis is made during Tier 1, the patient moves to Tier 2, where they participate in a telemedicine appointment to provide more medical history. If this does not result in a diagnosis, the patient moves to Tier 3 and Tier 4, the “research tiers,” where they undergo extensive in-person evaluation and genetic testing.
“The likelihood of discovering a new rare disease is high once they go to Tier 4,” Jiang says.
One exciting aspect of the center’s work will be the incorporation of artificial intelligence to increase diagnostic efficiency when reviewing patients’ histories in the earlier tiers. Reviewing patient medical records can be a time-consuming process, so Jiang’s collaborators are working to use AI to extract relevant information from the records.
“This information will guide us during the diagnostic evaluation and genetic data analysis and make the whole process more efficient,” Jiang says.
Rare disease research is difficult yet important
One of the biggest barriers in rare disease research is a lack of funding. Because there are so many rare diseases—an estimated 10,000 in the United States—and because the diseases are so uncommon, individual diseases are not seen as a public health priority. That reality is reflected in the funding allocated to study them, both from the government and from pharmaceutical companies that have the potential to develop new drugs.
“When pharma looks at a rare disease, if the disease has half a million patients, they are investing. If the disease has only 100 or, say, 1,000 patients, they’re less likely to invest,” Jiang says. “It’s a dilemma for the rare disease community. … It’s a lack of resources or even a lack of people interested to do the study.”
Joining the UDN and obtaining this grant to diagnose and study rare diseases are important steps both from a scientific and a clinical perspective.
“For a researcher, it all comes down to the biology and new disease pathophysiology. … People want to study these diseases to understand the basic science,” Jiang says. “For a physician, each patient, regardless of how rare their disease may be, is equal and deserves to be helped."
YDCoE is a large collaborative project involving many investigators, clinical consultants, and research collaborators from departments of Genetics (Caroline Hendry, Monkol Lek, Michele Spencer-Manzon, Hui Zhang, Shrikant Mane, Allen Bale), Pediatrics (Mustafa Khoka), Medicine (Emily Wang, Sakinah Suttiratana, Carol Oladele) and Biomedical Informatics and Data Science (Hua Xu and Mark Gerstein) at YSM, YNHH, and Fair Haven Community Health Care (Benjamin Oldfield).