Gladstone study shows TBX5 loss scrambles 3D DNA folding tied to congenital heart defects

SciTechDaily reported that Gladstone Institutes researchers found halving levels of the heart-development protein TBX5 can disrupt DNA looping and silence essential genes, offering a mechanism for why one faulty gene copy can cause serious congenital heart disease. Congenital heart disease is the most common birth defect, affecting about 1 in every 100 babies born each year. A child can inherit one healthy TBX5 copy and still develop defects if the other copy fails, a pattern called haploinsufficiency. The study, published in Science with DOI: 10.1126/science.adv5434 and dated 23 July 2026 in the article's reference block, shows TBX5 helps arrange DNA into the three-dimensional structure heart cells need. Senior authors Benoit Bruneau, director of the Gladstone Institute of Cardiovascular Disease, and Katie Pollard, director of the Gladstone Institute of Data Science and Biotechnology, used computational models on thousands of individual cells. Losing one gene copy destabilized genome organization across compartments, domains, and chromatin loops that bring enhancers into contact with genes. Bruneau said TBX5 is one example of a broader class of genes that cause birth defects when only one copy is lost, and that many defects may stem from the cell's 3D instruction manual folding the wrong way. The team plans to map when TBX5 begins organizing the genome in early heart development and whether other birth-defect proteins act similarly. Implication: A DNA-architecture explanation for haploinsufficiency points congenital heart research beyond simple gene dosage toward folding-based therapies.