Hemizygous deletion of 22q11 affects approximately 1:4000 live births and may give rise to many different malformations but classically results in a constellation of phenotypes that receive a diagnosis of DiGeorge syndrome or velocardiofacial syndrome. Particularly affected are the heart and great vessels, the endocrine glands of the neck, the face, the soft palate, and cognitive development. Although up to 50 genes may be deleted, it is haploinsufficiency of the transcription factor TBX1 that is thought to make the greatest contribution to the disorder. Mouse embryos are exquisitely sensitive to varying levels of Tbx1 mRNA, and Tbx1 is required in all three germ layers of the embryonic pharyngeal region for normal development. TBX1 controls cell proliferation and affects cellular differentiation in a cell autonomous fashion, but it also directs non-cell autonomous effects, most notably in the signaling between pharyngeal surface ectoderm and the rostral neural crest. TBX1 interacts with several signaling pathways, including fibroblast growth factor, retinoic acid, CTNNB1 (formerly known as β-catenin), and bone morphogenetic protein (BMP), and may regulate pathways by both DNA-binding and non-binding activity. In addition to the structural abnormalities seen in 22q11 deletion syndrome (DS) and Tbx1 mutant mouse models, patients reaching adolescence and adulthood have a predisposition to psychiatric illness. Whether this has a developmental basis and, if so, which genes are involved is an ongoing strand of research. Thus, knowledge of the genetic and developmental mechanisms underlying 22q11DS has the potential to inform about common disease as well as developmental defect.
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