TBX1 and the DiGeorge Syndrome Critical Region

Abstract

Abstract Congenital cardiovascular malformation is the most common class of birth defects and one of the three most common causes of death in the )rst year of life (Rubin et al., 1985). Abnormal gene dosage is the best understood genetic cause of congenital heart defects (CHDs). The most common genetic cause of CHDs is trisomy-21 (Down syndrome), which affects approximately 1 in 1000 fetuses and is associated with a 40% incidence of cardiac defects (Adams et al., 1981). Inappropriate gene dosage caused by gene deletions is also associated with congenital heart disease. Children with DiGeorge syndrome (DGS) or sequence, who display a recognizable spectrum of craniofacial anomalies, abnormal morphogenesis of the cardiac out%ow tract and great vessels (aorta, subclavian, pulmonary arteries), and thymic and parathyroid defects often have microdeletions of chromosome 22q11 (Driscoll et al., 1993). Identical chromosome 22q11 deletions have been identi)ed in patients with velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome (CAFS), and isolated CHDs (Goldmuntz et al., 1998). Deletion of this region on chromosome 22, called the “DiGeorge critical region” (DGCR), is the second most common known genetic cause of congenital heart disease (Goodship et al., 1998). The heterogeneous clinical manifestations of these 22q11 deletion syndromes have captured the interest and attention of clinical and molecular geneticists hoping to dissect the genetic basis of this human chromosomal haploinsuf)ciency.