SAN FRANCISCO—October 22, 2025—Nearly half of all babies born with Down syndrome face congenital heart defects, often involving serious malformations that require surgery in the first months of life.
For decades, scientists have known that having an extra copy of chromosome 21—the genetic cause of Down syndrome—was responsible, but they couldn't pin down which of its hundreds of genes were key for causing the heart problems.
Now, scientists at Gladstone Institutes have an answer. In a study published in Nature, the researchers leveraged stem cell science and artificial intelligence to discover that a gene called HMGN1 disrupts how DNA is packaged and regulated, and can throw off levels of hundreds of other molecules involved in healthy heart development. When the team removed the extra copy of HMGN1 from mice with Down syndrome, the animals no longer developed heart defects.
"This new knowledge could pave the way for treatments to help prevent heart malformations in people with Down syndrome and related heart defects, which would be a major win for patients and their families," says Deepak Srivastava, MD, president of Gladstone, where he is a senior investigator. Srivastava is also a pediatric cardiologist at UC San Francisco (UCSF).
A Hunt for the Cause
Down syndrome is the most common chromosomal disorder, affecting about one in 700 babies. Also known as trisomy 21, it's caused by having three, rather than two, copies of chromosome 21.
That extra chromosome leads to a higher risk of many health challenges, with heart issues among the most common. The likelihood of congenital heart defects—commonly, a hole in the wall of the heart's chambers—are 40 to 50 times greater in people with Down syndrome than in the general population.
Srivastava and his collaborators set out to uncover which of the hundreds of genes on chromosome 21 was responsible for the heart defects. To do so, they turned to individuals who are "mosaic" for trisomy 21, a rare situation in which some cells in the body have three copies of chromosome 21, and others have the usual two. Mosaic individuals do not have features of Down syndrome, but bear a high risk of having children with the condition.
Most of the time, researchers comparing healthy and Down syndrome cells must collect cells from two different individuals. But when they see differences in how the cells function, they can't be sure whether these are due to chromosome 21 or to other genetic variations between the individuals. Working with cells from people who have mosaic Down syndrome, this uncertainty is eliminated.
"Everything else in these cells was exactly the same, so this gave us a perfect, natural control experiment," says co-first author Sanjeev Ranade, PhD, previously a postdoctoral fellow in Srivastava's lab and now an assistant professor at Sanford Burnham Prebys Institute.
Using induced pluripotent stem (iPS) cell technology, the scientists took cell samples from the mosaic individuals and turned them into heart cells in the lab.
"The aha moment came when we found a striking difference in the heart cells with three copies of chromosome 21, compared to those with two copies," Srivastava says. "That made us wonder which gene on the chromosome was causing this dramatic shift in the cells."
Using a CRISPR-based technology that can precisely nudge genes to slightly higher activity, the researchers then boosted levels of each of the candidate genes on chromosome 21. They activated the genes, one at a time, in healthy cells containing the normal two copies of the chromosome, asking if any could mimic the problem seen in trisomy cells.
AI Brings Surprise Discovery
To analyze the resulting data and determine which healthy cells with one activated gene most resembled cells with trisomy 21, Srivastava's group teamed up with Katie Pollard, PhD, the L.K. Whittier director of the Gladstone Institute of Data Science and Biotechnology and a professor at UCSF.
Pollard and her colleagues used an artificial intelligence algorithm to model the differences between the healthy heart cells and those impacted by Down syndrome.
"The model allowed us to gain insights from the huge amount of data generated by the lab experiments," says Sean Whalen, PhD, principal staff research scientist in Pollard's lab. "As a result, we were able to predict that one gene, called HMGN1, made heart cells look like the abnormal cells in Down syndrome. Surprisingly, this gene wasn't on anyone's radar as one that could cause the disorder."
From Mice to Possible Medicines
Once the scientists identified HMGN1, they moved to validate the prediction with animal studies. In a mouse model of Down syndrome, the team showed that reducing HMGN1 to two copies restored normal heart development.
"When we reduced the levels of HMGN1, heart defects disappeared," says Feiya Li, PhD, a postdoctoral fellow in Srivastava's lab and co-first author of the study. "It was a powerful indication that three copies of this gene are needed to cause the heart defects in Down syndrome."
The scientists believe that while increased levels of HMGN1 are necessary for the cardiac defects, other genes are also likely involved, including a gene called DYRK1. Srivastava's team is now testing whether the combination of these two genes is sufficient to cause cardiac defects in mice.
The new findings could one day open the door to therapies that dial down HMGN1 activity, potentially with a treatment delivered to the mother. It also provides a blueprint for investigating other disorders caused by altered numbers of chromosomes, which have been difficult to study.
"Our work shows the power of combining cutting-edge genomics with advanced computational modeling," Pollard says. "We now have a roadmap not only for understanding heart defects in Down syndrome, but for studying the root causes of other diseases caused by extra or missing chromosomes."
About Gladstone Institutes
Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is done, funds big ideas, and attracts the brightest minds.
