TBX5 DNA misfolding mechanism discovered

Researchers at Gladstone Institutes published a study in Science on July 23, 2026, revealing that the TBX5 gene, linked to congenital heart defects, plays a critical role in folding DNA into the three-dimensional architecture needed for heart cell function. The study showed that losing even one copy of TBX5 causes the collapse of the heart's 3D DNA organization at all levels—compartments, domains, and chromatin loops—leading to misfolding and disease. This provides a new mechanism for haploinsufficiency, where one functional copy of a gene is insufficient for normal development. The findings suggest that many birth defects attributed to genetic mutations may actually be caused by 3D misfolding of DNA. The research was supported by the United States — National Institutes of Health, the United States — California Institute for Regenerative Medicine, the United States — National Science Foundation, the Roddenberry Foundation, and the Saving Tiny Hearts Society.