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In animal models,Nipbldeficiency phenocopies gene expression changes and birth defects seen in Cornelia de Lange syndrome, the most common cause of which isNipblhaploinsufficiency. Previous studies inNipbl^+/−mice suggested that heart development is abnormal as soon as cardiogenic tissue is formed. To investigate this, we performed single-cell RNA sequencing on wild-type andNipbl^+/−mouse embryos at gastrulation and early cardiac crescent stages.Nipbl^+/−embryos had fewer mesoderm cells than wild-type and altered proportions of mesodermal cell subpopulations. These findings were associated with underexpression of genes implicated in driving specific mesodermal lineages. In addition,Nanogwas found to be overexpressed in all germ layers, and many gene expression changes observed inNipbl^+/−embryos could be attributed toNanogoverexpression. These findings establish a link betweenNipbldeficiency,Nanogoverexpression, and gene expression dysregulation/lineage misallocation, which ultimately manifest as birth defects inNipbl^+/−animals and Cornelia de Lange syndrome.