This article presents research identifying a key genetic contributor to congenital heart defects (CHDs) associated with Down syndrome, or trisomy 21. Using human induced pluripotent stem cells (hiPSCs) and a mouse model of Down syndrome, the authors investigated dosage-sensitive genes on chromosome 21 that disrupt heart development, specifically focusing on the atrioventricular canal (AVC) defects. Through single-cell RNA sequencing (scRNA-seq) and a CRISPR-activation (CRISPRa) screen, the study isolates the epigenetic regulator HMGN1 as the critical gene whose triplication causes AVC cardiomyocytes to shift toward a ventricular cell state. Crucially, the researchers demonstrate that reducing the dosage of Hmgn1 in the mouse model rescues both the abnormal gene expression profile and the increased incidence of cardiac septal defects.

References:

• Ranade S S, Li F, Whalen S, et al. Myocardial reprogramming by HMGN1 underlies heart defects in trisomy 21[J]. Nature, 2025: 1-9.