After decades of uncertainty, researchers have finally identified the gene responsible for congenital heart defects in children with Down syndrome — and found that correcting it can prevent these defects in mice.
The study, conducted by scientists at the Gladstone Institutes in the U.S. and published in Nature on October 22, was reported by EurekAlert. Nearly half of all babies born with Down syndrome suffer from serious heart abnormalities that often require surgery in early infancy.
Although scientists have long known that an extra copy of chromosome 21 causes Down syndrome, the specific genes behind the heart problems remained unknown until now.
Using stem cell research and artificial intelligence, the team discovered that a gene called HMGN1 disrupts the organization and regulation of DNA, affecting hundreds of molecules involved in normal heart development. When researchers removed the extra copy of this gene in mice with Down syndrome, the animals no longer developed heart defects.
According to Dr. Deepak Srivastava, a pediatric cardiologist at the University of California, San Francisco, and president of the Gladstone Institute, this discovery could pave the way for treatments to prevent heart defects in people with Down syndrome — a major breakthrough for patients and their families.
Down syndrome, or trisomy 21, is the most common chromosomal disorder, affecting about one in every 700 births. It increases the risk of numerous health problems, with heart defects among the most common, occurring 40 to 50 times more frequently than in the general population.
The researchers worked with cells from individuals with mosaic Down syndrome, a rare condition in which some cells contain three copies of chromosome 21 while others have two. These individuals often show mild or no typical Down syndrome traits but have a high risk of passing the condition to their children.
The scientists converted these cells into heart cells in the lab, where they noticed clear differences between those with two and three copies of chromosome 21. This prompted them to identify the gene driving such dramatic cellular changes.
Using the CRISPR gene-editing technique, they selectively activated genes on chromosome 21 one by one in normal cells, to see which could reproduce the abnormalities observed in trisomic cells. They also used AI algorithms to model differences between healthy and affected heart cells.
Once HMGN1 was pinpointed, the researchers confirmed the findings in animal studies. In a mouse model of Down syndrome, reducing the number of HMGN1 copies from three to two restored normal heart development.
The scientists believe that while elevated HMGN1 levels are a key factor in these defects, other genes such as DYRK1 may also contribute. They are now testing whether combining these genes causes similar effects — a step that could one day lead to therapies to suppress their activity, potentially even through prenatal treatments given to mothers
