DiGeorge syndrome (DGS; also known as Velo-cardio-facial syndrome) is associated with hemizygous deletion of a region of human chromosome 22q11, causing a range of abnormalities including cardiovascular defects, hypoplasia of the thymus and parathyroid gland, and craniofacial abnormalities.

Three research groups have identified the TBX1 gene, a member of the T-box family of transcription factors, as a key determinant of the DGS phenotype. Merscher et al. (Cell 2001, 104:619-629) and Lindsay et al. (Nature 2001, 410:97-101) used chromosomal engineering induced using the Cre recombinase and artificial chromosome transgenesis to localize the haplosufficiency region on the mouse chromosome, chromosome 16, that corresponds to the human disease region.

This region contains the TBX1 gene, expression of which in the pharyngeal arches makes it a strong candidate gene for DGS. Both groups, together with Jerome and Papaioannou (Nature Genetics 2001, 27:286-291), show that TBX1 haploinsufficiency in mice causes cardiovascular defects and anomalies of the heart outflow tract that resemble the human syndrome. Furthermore, TBX1-/- mice also display thymus and parathyroid abnormalities, as seen in DGS patients.

TBX1 is the first dosage-sensitive gene to be identified in the deleted 22q11 region. It remains to be established whether TBX1 mutation alone accounts for DiGeorge syndrome, and whether human patients differ from the mouse models in their sensitivity to TBX1 haploinsufficiency.