22q11.2 deletion is the most common microdeletion syndrome that has been reported in humans. It is also the most common syndrome associated with cleft palate and the most common syndrome associated with conotruncal anomalies (Shprintzen et al., 2005). Microdeletion syndromes are genetic disorders caused by the loss of a small chromosome segment contains multiple genes, but that is too small to be detected via the 400-band standard metaphase karyotype. 22q11.2 deletion is commonly thought of as being equivalent with DiGeorge syndrome.

DiGeorge syndrome was first described in 1965 by Dr. Angelo DiGeorge as a developmental field defect that affected structures derived from the 3rd and 4th pharyngeal arches. It is now known that 22q11.2 deletion is actually associated with a variety of different syndromes that appear to be phenotypic variants of the same disorder. 22q11.2 deletion encompasses DiGeorge syndrome, velocardiofacial syndrome (VCFS), conotruncal anomaly face syndrome, Opitz G/BBB syndrome, and Cayler cardiofacial syndrome, which is also known as asymmetric crying facies syndrome. Ninety percent of patients with DiGeorge syndrome who have an apparently normal karyotype actually have a microdeletion of chromosome 22q11.2 (Figure 139-1). This was not appreciated until the development of molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH).

The clinical findings of 22q11.2 deletion are highly variable, both between families and within families (Yamagishi and Srivastava, 2003). Approximately 75% of patients with 22q11.2 deletion have congenital heart disease, most commonly abnormalities involving the outflow tracts and the aortic arch. Patients with this deletion have a characteristic facial appearance, immunodeficiency due to thymic hypoplasia, velopharyngeal dysfunction either with or without cleft palate, hypocalcemia due to hypoparathyroidism, developmental and behavioral problems, and psychiatric disorders in adulthood (Yamagishi and Srivastava, 2003).

The minimum incidence of 22q11.2 deletion is 1 in 6395 livebirths, as described in the Flemish region of Belgium (DeVriendt et al., 1998a). In 2003, Botto et al. performed a population-based study, using matched records from the metropolitan Atlanta congenital defects program, the Sibley Heart Center, and the Division of Medical Genetics at Emory University School of Medicine. This group found 43 children with cytogenetic laboratory confirmed 22q11.2 deletion in a total population of 255,849 births. This gave an overall prevalence of 1 in 5950 births, with a slight racial difference observed. The prevalence was 1 in 6000 among white, black, and Asian individuals, and 1 in 3800 among Hispanics. The reason for the discrepancy was not known. The importance of the cytogenetic deletion was illustrated by the fact that 22q11.2 deletion was shown to contribute to 1 in 68 cases of congenital heart defects, 1 in 2 cases of interrupted aortic arch type B, 1 in 5 cases of truncus arteriosus, and 1 in 8 cases of tetralogy of Fallot.

A deletion of 22q11.2 should be considered in fetuses with specific types of isolated congenital heart disease, such as tetralogy of Fallot, truncus arteriosus (Figure 139-2), aor-tic arch anomalies, absent pulmonary valve, or ventricular septal defect with pulmonary atresia or aortic arch anomalies (Goldmuntz, 2005). Deletion 22q11.2 should also be considered in any fetus with congenital heart disease and some other feature that has been described in fetuses with this condition, such as polyhydramnios (DeVriendt et al., 1998b), vertebral anomalies, holoprosencephaly, spina bifida, or renal anomalies (Stewart et al., 1999).

In one study, all fetuses with sonographically detected cardiac anomalies, an unremarkable family history and a normal metaphase karyotype were studied specifically for the incidence of the 22q11.2 deletion over a 3-year period (Manji et al., 2001). A total of 46 cases were studied by FISH. Five out of the 46 cases (10.8%) had the deletion. The fetal sonographic abnormalities found included tetralogy of Fallot, atrial ventricular canal defect, VSD with truncus ar-teriosus, and VSD and ASD. Parental chromosome studies showed that one case was maternally inherited, three represented de novo mutations, and in one case the parents declined cytogenetic testing. In another study, 261 consecutive fetuses with a conotruncal cardiac malformation and a normal karyotype were studied for the presence of the 22q11.2 microdeletion (Table 139-1) (Boudjemline et al., 2001). A microdeletion was found in 54 of 261 fetuses (20.7%). Recently, multiple studies have appeared that have taken specific fetal cardiac anomalies and analyzed the relative percentage of microdeletions present. For example, Galindo et al. (2006) studied 14 cases of the rare malformation of absent pulmonary valve; 3 of these had microdeletion 22q11.2. Similarly, in a study of 71 cases of antenatally presenting right aortic arch, 7 cases (10%) had the microdeletion (Berg et al., 2006). However, all of these seven cases had associated extrac-ardiac anomalies. In a large study of 92 fetuses with tetralogy of Fallot that had cytogenetic studies performed, 15 had evidence of 22q11.2 microdeletion (16.3%) (Poon et al., 2007).