By Deborah Borfitz

August 13, 2026 | Medical conditions vary widely in presentation, progression, and treatment response, with Down syndrome standing out as one of the most variable of all. The genetic occurrence, caused by an extra copy of chromosome 21, is widely considered one of the most heterogenous conditions, with highly variable clinical presentation from person to person. 

A recently published multiomics analysis required only 356 participants to analyze 100 clinical phenotypes more common in people with Down syndrome (Nature Communications, DOI: 10.1038/s41467-026-72946-z). Researchers ranked all co-occurring conditions, to see which ones had the strongest footprint on physiology, and, surprisingly, obesity came in number one in terms of effects on the proteome and metabolome, according to Joaquín Espinosa, Ph.D., professor of pharmacology at the University of Colorado Anschutz and executive director of its Linda Crnic Institute for Down Syndrome, the research affiliate of the Global Down Syndrome Foundation and the world’s largest center for Down syndrome research.  

Another notable finding was that congenital heart defects have lifelong physiological consequences on the transcriptome and immune profile, despite being spontaneously resolved or surgically repaired in the first months of life. Molecular profiling revealed “lingering residual cardiac stress,” Espinosa reports. Among the co-occurring neurological conditions, seizures were found to have the greatest impact on multiomics signatures.  

“People with Down syndrome are living longer, healthier lives than ever before and this type of research will lead to further gains in [their] quality of life and life expectancy ... leading to a future where they will be capable of things that we cannot even imagine,” he says. “We’re now seeing people with Down syndrome on TV, in movies, in sports, in art, and we want to take that to the next level. If we can figure out how to keep them healthy and thriving, they’ll be capable of great contributions.”     

A decade ago, Espinosa launched the Crnic Institute's Human Trisome Project that has become the largest cohort study of people with Down syndrome. One of its key goals is to enable a precision medicine platform for the management of the condition, and the latest paper is one in a series toward that end. 

Few Commonalities 

Although all people with Down syndrome share a common genetic aberration, “that’s about all they have in common,” Espinosa stresses. “At the end of the day, we should think of Down syndrome as a condition that needs to be studied under the lens of personalized medicine.” 

Beyond shared changes in gene expression caused by the extra copy of chromosome 21, other unknown factors modulate the clinical presentation of Down syndrome, he says. Those multitude of factors could include other differences in their genetic makeup, epigenetics, metabolism, immune profiles, diet and lifestyle, and access to medical care. 

The latest paper is anchored by the hypothesis that multiomics would reveal the differences, and they would depend on the co-occurring conditions affecting individuals. It is a first-of-its-kind study trying to tease out the heterogeneity among persons with Down syndrome, fully expecting “novel biosignatures applying to various fractions of the cohort,” says Espinosa. 

Espinosa became director of the Crnic Institute in 2017. Prior to that, he was a molecular oncologist with a long track record of contributions to the field of cancer research. In assuming his new role focused on the study of Down syndrome, he was intent on bringing along the best approaches from the field of oncology where it is well known that no two tumors are the same, he says. They are separated by molecular differences that determine choice and response to treatment.   

Precision, personalized medicine is not yet a reality for Down syndrome, but the Human Trisome Project has enabled progress in that direction, says Espinosa. Interconnected streams of research include a massive natural history study, biorepository creation, and studies about how Down syndrome biology changes with age, as well as multiomics mapping of blood samples to connect clinical traits. 

Neglected Needs 

Individuals with Down syndrome and their families are in the same sort of position as cancer patients when it comes to “uncertainty about their upcoming trajectory,” says Espinosa. But that’s where the similarities end. 

Cancer is generally an acquired condition, and precision medicine tools exist to examine tumors and choose the therapies that are more likely to work, he continues. The molecular-level interrogation is ongoing because tumors evolve, and therapeutic approaches need periodic tweaking.  

For individuals born with Down syndrome, heterogeneity is present from day one, says Espinosa. Nearly half of babies born with the genetic condition also have a congenital heart defect. Another 50% of individuals with Down syndrome acquire autoimmune thyroid disease. Up to 20% have autism diagnosed in the first decade of life.

These co-occurring conditions are distinct from the “conserved effects” of the extra copy of chromosome 21, Espinosa says. Pretty much everyone with Down syndrome has some degree of immune dysregulation, putting them at a high risk for both chronic autoinflammation and autoimmune disorders. At the time of clinical examination, however, “50% of them may have autoimmune thyroid disease, 10% may have celiac disease, [and] about 35% may have immune skin disorders.”   

Down syndrome, unlike cancer, had not attracted hefty investments in research until the 2018 launch of the INCLUDE Project by the National Institutes of Health, he notes. It therefore lacks the molecular profiling necessary to identify unique subgroups and monitor changes in patients as they age to keep them matched to the best available treatments. 

To make matters worse, there is also a “massive shortage” of Down syndrome experts in the clinic, Espinosa reports, which is tied to historical neglect of the condition as a topic of study. “If you go to a school of medicine even to this day, you’ll get very little training, if any, on Down syndrome.” 

People with Down syndrome were routinely institutionalized through the 1970s and denied proper access to basic medical care and society, he points out. “There was a perception at some point that the population with Down syndrome would eventually disappear due to prenatal screening and elective [pregnancy] terminations, and that has not been the case. There are more people with Down syndrome alive today than ever before,” and in the U.S. the condition occurs in about 1 in every 700 live births.  

Down syndrome being a multi-organ, multi-system condition, its proper management requires a multidisciplinary team, says Espinosa. The needed expertise may include developmental-behavioral, endocrinology, rheumatology, immunology, neurology, and otolaryngology specialists, depending on the co-occurring conditions. Only a few multidisciplinary clinics exist in the entire country.  

Clinical Trials 

The Crnic Institute is now on its third clinical trial testing immune therapies for Down syndrome, Espinosa shares. As the latest multiomics analysis shows, immune dysregulation is tied to a multitude of co-occurring conditions. 

It was only a few years ago that Down Syndrome Regression Disorder, which causes a sudden loss of neurological function in otherwise healthy individuals with Down syndrome, was linked to immune dysregulation. The condition occurs in a small percentage of people with Down syndrome, and the cluster of symptoms presents over the course of only a few days or weeks, says Espinosa. 

Affected individuals lose speech, sleep, and personality, and become highly dependent on their caregivers to manage the tasks necessary for daily living. “We don’t know what’s causing it ... [but] there is very strong research that this may be associated with an inflammatory process affecting brain function,” he adds.  

About 10 years ago, the Crnic Institute published a study finding that Down syndrome increases interferon signaling that leads to chronic immune dysregulation, highlighting the therapeutic value of immune-modulatory strategies (eLife, DOI: 10.7554/eLife.16220). In persons with Down syndrome, the interferon response—the part of the immune system that blocks viral replication—is always on and so they are in a perpetual state of inflammation, Espinosa explains. 

The good news is that JAK inhibitors, a popular class of medicines for the treatment of many autoimmune and autoinflammatory conditions, lowers the interferon response. Over much of the last decade, Crnic Institute researchers have been testing the idea of repurposing the JAK inhibitor tofacitinib (Xeljanz) as a treatment for some of the co-occurring conditions seen in people with Down syndrome. 

The first clinical trial was completed successfully at the end of 2024, confirming tofacitinib was safe when used for treating inflammatory skin conditions in Down syndrome (eLife, DOI: 10.7554/eLife.99323). A second trial just finished that is focused on Down syndrome regression disorder, Espinosa says, and a third trial currently open for recruitment will be looking at the potential benefits of modulating the immune system for anyone with Down syndrome. 

Co-occurring conditions that could be associated with this heightened inflammatory state include pulmonary hypertension, celiac disease, type I diabetes, and other immune-driven conditions that could perhaps be treated with JAK inhibitors, says Espinosa. 

Tofacitinib was the first JAK inhibitor to become generic earlier this year, he says. Research at the Crnic Institute using the drug has been funded by the National Institutes of Health, the Anschutz Acceleration Initiative, the Global Down Syndrome Foundation, and the Anna and John J. Sie Foundation.  

Lifelong Surveillance 

From Espinosa’s vantage point, the future for people with Down syndrome will be marked by a shift to precision medicine based on an understanding of the root molecular causes of the many conditions they may be facing over the course of a lifetime. This means from birth onward molecular data derived from their blood, saliva, or skin will be used to identify their position on the developmental trajectory and risk for different co-occurring conditions and treating them if they emerge. 

Individuals with Down syndrome will require more frequent and targeted screening than the general population where people are typically at risk for only one or two major health conditions at a time. The biomedical research enterprise would have to sign into this highly tailored, patient-specific scenario, which is already happening for certain co-occurring conditions, Espinosa says. 

Approved blood tests are now on the market for the early diagnosis of Alzheimer’s disease that are based on a couple of proteins in the blood serving as proxies for amyloid plaques in the brain, he offers as an example. Because Alzheimer's begins much earlier in people with Down syndrome, often in their early 50s, they have become of primary interest for early detection research.