Cardiac Organoids Uncover an Association of CHD7 Deficiency with Congenital Heart Disease

CHD7 (Chromodomain helicase DNA-binding protein 7) encodes an ATP-dependent chromatin remodeler, and pathogenic disruption of CHD7 underlies CHARGE syndrome(Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genital abnormalities, Ear abnormalities syndrome), a congenital disorder frequently accompanied by complex cardiac malformations. However, how CHD7 contributes to human cardiogenesis remains poorly defined. Here, we use multi-chamber cardiac organoids derived from human embryonic stem cells, which capture key features of early cardiac morphogenesis and regional lineage patterning, to interrogate CHD7 function. CHD7 loss leads to attenuation of cardiac progenitor gene programs, disrupted chamber organization, reduced efficiency of cardiomyocyte differentiation, and markedly impaired contractile function. Bulk RNA sequencing further reveals broad misregulation of transcriptional modules involved in cardiogenic signaling, regional progenitor patterning, and myocardial maturation. Together, these data establish a human organoid framework for modelling CHD7-associated congenital heart disease and identify CHD7 as a key regulator of cardiac morphogenesis and the acquisition of functional cardiomyocyte properties.