New Study Reveals How TBX5 Gene Disruption Contributes to Congenital Heart Disease

Researchers at the Gladstone Institutes have uncovered new insights into congenital heart disease, the most prevalent birth defect, affecting approximately 1 in 100 infants each year. Their study, published in the journal Science, highlights the role of the TBX5 gene, which is critical for heart development and helps organize DNA into a three-dimensional structure necessary for heart cells to function properly.

The gene TBX5 has long been recognized as a regulator of heart development; however, this research identifies an additional function beyond gene activity control. It establishes that losing even one copy of TBX5 can significantly disrupt the organization of DNA within heart cells, consequently altering the expression of many other genes involved in heart development.

Benoit Bruneau, PhD, director of the Gladstone Institute of Cardiovascular Disease and senior author of the study, remarked, “TBX5 is just one example of a broader class of genes that cause birth defects when only one copy is lost. What’s exciting about our findings is they suggest many different birth defects might happen for the same reason: the cell’s 3D instruction manual simply gets folded the wrong way.”

Disruption in DNA Organization

The researchers conducted experiments with human stem cells, directing them to become heart muscle cells while manipulating the levels of TBX5. They utilized advanced computational models and high-resolution 3D mapping techniques to analyze the DNA structure at fine detail, revealing that the loss of TBX5 led to a collapse in the organization of the heart’s DNA across all structural levels.

Shuzhen Kuang, PhD, a first author of the study, noted, “Using the custom computational approaches we developed, we were able to see for the first time how the loss of TBX5 triggers the total collapse of the heart’s 3D DNA organization.”

The research found that TBX5 operates similarly to a GPS for a molecular motor called cohesin, guiding it to specific DNA locations to form chromatin loops that connect genes with their enhancers. A reduction in TBX5 levels leads to improper DNA folding, potentially causing critical genes essential for heart development to fail to activate.

Variability Among Heart Cells

The study also revealed that individual heart cells respond differently to the loss of TBX5, indicating variations between atrial and ventricular cells. Zoe Grant, PhD, another first author, explained, “This could help explain why people with the same mutation can have different heart defects.”

Despite focusing on congenital heart disease, researchers believe the mechanisms identified may also apply to other developmental disorders. Bruneau added, “We believe we’ve uncovered a new mechanism of disease… many birth defects currently attributed to genetic mutations may actually be caused by the 3D misfolding of DNA.”

The team is aiming to further investigate when TBX5 begins organizing the genome during early heart development and whether other proteins linked to birth defects influence DNA folding in similar ways.

The study titled “Dose-dependent sensitivity of human three-dimensional chromatin to a heart disease-linked transcription factor” was published on July 23, 2026. Research was supported by several organizations, including the National Institutes of Health and the California Institute for Regenerative Medicine.