About 97% of patients with DGS/VCFS have either a common recurrent deletion of approximately 3 Mb or a smaller, less common, 1.5-Mb nested deletion (Carlson et al., 1997; Ben-Shachar et al., 2008). Rauch et al. (1999) reported an ... About 97% of patients with DGS/VCFS have either a common recurrent deletion of approximately 3 Mb or a smaller, less common, 1.5-Mb nested deletion (Carlson et al., 1997; Ben-Shachar et al., 2008). Rauch et al. (1999) reported an infant girl with interrupted aortic arch, truncus arteriosus, a T-cell deficiency, and Pseudomonas aeruginosa sepsis. Dysmorphic features included hypoplasia of halluces and toenails, choanal stenosis, retrognathia, and short squared ears with simple overfolded helices. She died neonatally after surgical repair of the congenital heart defect. The proband's mother and sister had subtle anomalies. The mother had external strabismus, retrognathia, posteriorly angulated ears, broad neck with low posterior hairline, short 5th fingers, and a high-arched palate. The 12-year-old sister showed mild retrognathia, thin vermilion border of the upper lip, low-set, posteriorly angulated ears with overfolded helices, high-arched palate, and mild muscular hypotonia. Both the mother and sister had a history of recurrent bronchitis, but immunologic investigations were normal. Both also had mild learning difficulties. The brother and father were unaffected. Echocardiographic, immunologic, endocrine, and pharyngoscopic studies in the parents and sibs of the patient did not show any abnormalities. FISH analysis of the proband, mother, and sister detected a heterozygous chromosome 22q11.2 deletion that was distal to the common 3-Mb deletion region. Rauch et al. (1999) noted that the facial gestalt of the affected individuals differed from that observed in DGS and VCFS. Rauch et al. (2005) identified distal deletions of chromosome 22q11.2 in 3 (5%) of 63 patients with only mildly suggestive features of DGS/VCFS. One of the deletions was nested within the common 3-Mb region, and this patient showed speech delay, mild hypotonia, frequent infections, a small mouth, mild retrognathia, and mild ptosis. He was mildly mentally retarded. A second patient had valvular pulmonic stenosis, ventricular septal defect, persistent foramen ovale, and persistent ductus arteriosus. Her appearance and psychomotor development was normal, and only very careful investigation disclosed minimal broad folding of the right helix and somewhat widely spaced inverted nipples. Her healthy father, who had narrow palpebral fissures and low-set ears, was shown to carry the same deletion. Another patient was referred at the age of 7.5 years with a diagnosis of CHARGE syndrome (214800) based on bilateral choanal atresia, preauricular tag, hypoplastic irides, small ventricular septal defect, and conductive hearing loss. She also had frequent infections, strabismus, hyperopia, and learning difficulties with a low normal average IQ of 85. The deletion was excluded in both healthy parents. Using array-based comparative genomic hybridization (CGH) analysis, Ben-Shachar et al. (2008) detected 6 unrelated cases of 22q11.2 deletion located distal to the common 3-Mb deletion region. Further analyses revealed that the rearrangements had clustered breakpoints and a recurrent deletion. Parental fluorescence in situ hybridization (FISH) analyses revealed that none of the available parents had the deletion, indicating de novo events. All patients presented with characteristic facial dysmorphic features including arched eyebrows, deep-set eyes, a smooth philtrum, a thin upper lip, hypoplastic alae nasi, and a small, pointed chin. A history of prematurity, prenatal and postnatal growth delay, developmental delay, and mild skeletal abnormalities was frequent among the patients. Two patients had a cardiovascular malformation; one had truncus arteriosus and another had bicuspid aortic valve. A single patient had cleft palate. Ben-Shachar et al. (2008) concluded that distal deletions of chromosome 22q11.2 between LCR22-4 and LCR22-6, although they share some characteristic features with DGS/VCFS, represent a novel genomic disorder distinct genomically and clinically from the well-known DGS/VCF deletion syndromes. Tan et al. (2011) reported 5 unrelated Caucasian patients with copy number variations affecting distal 22q11.2 as determined by microarray analysis. These individuals were ascertained because of congenital malformations, developmental delay, or both. Three patients had deletions of 1.1 Mb, 3.2 Mb, and 247 kb, respectively, and 2 had duplications of 5.6 Mb and 1.87 Mb, respectively. None of the breakpoints was the same, although many had a proximal breakpoint within the D(4) low copy repeat sequence. One of the deletions was inherited from a phenotypically normal mother, 1 of the duplications was inherited from a normal father who had a broad forehead and mild downslanting palpebral fissures, and the other duplication was present in other phenotypically normal family members. The phenotypes were highly variable. One patient with a deletion had cardiac dextrorotation, diaphragmatic hernia, and uterine didelphys, whereas another had Goldenhar syndrome. One patient with distal duplication had tetralogy of Fallot and the other had frontomedial polymicrogyria and callosal agenesis.