HYPOPLASIA OF THYMUS AND PARATHYROIDS
DGCR, INCLUDED
CATCH22, INCLUDED
TAKAO VCF SYNDROME, INCLUDED
THIRD AND FOURTH PHARYNGEAL POUCH SYNDROME DIGEORGE SYNDROME CHROMOSOME REGION, INCLUDED
DGS
CHROMOSOME 22q11.2 DELETION SYNDROME
DiGeorge syndrome (DGS) comprises hypocalcemia arising from parathyroid hypoplasia, thymic hypoplasia, and outflow tract defects of the heart. Disturbance of cervical neural crest migration into the derivatives of the pharyngeal arches and pouches can account for the phenotype. ... DiGeorge syndrome (DGS) comprises hypocalcemia arising from parathyroid hypoplasia, thymic hypoplasia, and outflow tract defects of the heart. Disturbance of cervical neural crest migration into the derivatives of the pharyngeal arches and pouches can account for the phenotype. Most cases result from a deletion of chromosome 22q11.2 (the DiGeorge syndrome chromosome region, or DGCR). Several genes are lost including the putative transcription factor TUPLE1 which is expressed in the appropriate distribution. This deletion may present with a variety of phenotypes: Shprintzen, or velocardiofacial, syndrome (VCFS; 192430); conotruncal anomaly face (or Takao syndrome); and isolated outflow tract defects of the heart including tetralogy of Fallot, truncus arteriosus, and interrupted aortic arch. A collective acronym CATCH22 has been proposed for these differing presentations. A small number of cases of DGS have defects in other chromosomes, notably 10p13 (see 601362). In the mouse, a transgenic Hox A3 (Hox 1.5) knockout produces a phenotype similar to DGS as do the teratogens retinoic acid and alcohol.
DiGeorge syndrome is characterized by neonatal hypocalcemia, which may present as tetany or seizures, due to hypoplasia of the parathyroid glands, and susceptibility to infection due to a deficit of T cells. The immune deficit is caused by ... DiGeorge syndrome is characterized by neonatal hypocalcemia, which may present as tetany or seizures, due to hypoplasia of the parathyroid glands, and susceptibility to infection due to a deficit of T cells. The immune deficit is caused by hypoplasia or aplasia of the thymus gland. A variety of cardiac malformations are seen in particular affecting the outflow tract. These include tetralogy of Fallot, type B interrupted aortic arch, truncus arteriosus, right aortic arch and aberrant right subclavian artery. In infancy, micrognathia may be present. The ears are typically low set and deficient in the vertical diameter with abnormal folding of the pinna. Telecanthus with short palpebral fissures is seen. Both upward and downward slanting eyes have been described. The philtrum is short and the mouth relatively small. In the older child the features overlap Shprintzen syndrome (velocardiofacial syndrome) with a rather bulbous nose and square nasal tip and hypernasal speech associated with submucous or overt palatal clefting. Cases presenting later tend to have a milder spectrum of cardiac defect with ventricular septal defect being common. Short stature and variable mild to moderate learning difficulties are common. A variety of psychiatric disorders have been described in a small proportion of adult cases of velocardiofacial syndrome. These have included paranoid schizophrenia and major depressive illness. Clinical features seen more rarely include hypothyroidism, cleft lip, and deafness. Goodship et al. (1995) described monozygotic twin brothers with precisely the same 22q11.2 deletion but somewhat discordant clinical phenotype. Both twins had a small mouth, square nasal tip, short palpebral fissures, and small ears with deficient upper helices. Twin 1 had bilateral hair whorls and twin 2 had a right-sided hair whorl. Toes 4 and 5 were curled under bilaterally in both boys, this being more marked in twin 1. The twins were said to have had a single placenta although the findings of a detailed examination were not recorded. Twin 1 weighed 2,200 g and twin 2 weighed 2,800 g. Twin 1 had tetralogy of Fallot, which was repaired at 1 year of age. Twin 2 had a normal cardiovascular system. Twin 1 started taking steps at 24 months of age, while his brother stood at 13 months and walked steadily at 18 months. These observations indicated to Goodship et al. (1995) that differences in deletion size and modifying genetic loci are not responsible for all the phenotypic differences observed in CATCH22. Vincent et al. (1999) reported the case of female monozygotic twins with 22q11 deletions. The twins shared facial characteristics of DGS/VCFS and immunologic defect. However, only one, who died on day 5, had a cardiac defect, comprised of an interrupted aortic arch with a ventricular septal defect, a truncus arteriosus, and a large arterial duct. The authors stated that this was the fourth report of a discrepant cardiac status between monozygotic twins harboring 22q11 deletions. Wilson et al. (1992) looked for deletions in 9 families with 2 or more cases of outflow tract heart defects. In 5 of the families, chromosome 22 deletions were detected in all living affected persons studied and also in the clinically normal father of 3 affected children. The deletion was transmitted from parents to offspring and was associated with an increase in the severity of cardiac defects. No deletions were found in 4 families in which the parents were normal and affected sibs had anatomically identical defects, presumably an autosomal recessive form of congenital heart defect. Fokstuen et al. (1998) analyzed 110 patients with nonselective syndromic or isolated nonfamilial congenital heart malformations by fluorescence in situ hybridization using the D22S75 DGS region probe. A 22q11.2 microdeletion was detected in 9 of 51 (17.6%) syndromic patients. Five were of maternal origin and 4 of paternal origin. None of the 59 patients with isolated congenital cardiac defect had the 22q11.2 deletion. In a study of 157 consecutively catheterized patients with isolated, nonsyndromic cardiac defects, and 25 patients with cardiac malformation and additional abnormalities (10 of whom had been clinically diagnosed as DiGeorge syndrome or velocardiofacial syndrome), Borgmann et al. (1999) found the 22q11.2 microdeletion only in the latter group. Jawad et al. (2001) studied 195 patients with chromosome 22q11 deletion syndrome and found that diminished T-cell counts in the peripheral blood are common. The pattern of changes seen with aging in normal control patients was also seen in patients with the chromosome 22q11.2 deletion syndrome, although the decline in T cells was blunted. Autoimmune disease was seen in most age groups, although the types of disorders varied according to age. Infections were also common in older patients, although they were seldom life-threatening. Juvenile rheumatoid arthritis with onset between 1.5 and 6 years of age was seen in 4 of the 195 patients; idiopathic thrombocytopenia purpura with onset at 1 to 8 years of age was seen in 8 of 195 patients; autoimmune hemolytic anemia, psoriasis, vitiligo, inflammatory bowel disease, adult rheumatoid arthritis, and rheumatic fever with chorea were each seen in 1 patient of the 195 patients sampled. Kawame et al. (2001) reported 5 patients with chromosome 22q11.2 deletion that manifested Graves disease between the ages of 27 months and 16 years, and suggested that Graves disease may be part of the clinical spectrum of this disorder. Bassett et al. (2005) described the phenotypic features of 78 adults with 22q11 deletion syndrome and identified 43 distinct features present in more than 5% of patients. Common characteristic features included intellectual disabilities (92.3%), hypocalcemia (64%), palatal anomalies (42%), and cardiovascular anomalies (25.8%). Other less commonly appreciated features included obesity (35%), hypothyroidism (20.5%), hearing deficits (28%), cholelithiasis (19%), scoliosis (47%), and dermatologic abnormalities (severe acne, 23%; seborrhea, 35%). Significantly, schizophrenia was present in 22.6% of patients. Maalouf et al. (2004) reported an African American male diagnosed at age 32 years with dysgenesis of the parathyroid glands due to a chromosome 22 microdeletion. Symptomatic hypocalcemia did not develop until age 14 years, a few weeks after initiation of anticonvulsant therapy for generalized tonic-clonic seizures. Because of the timing for onset of symptomatic hypocalcemia, it was presumed that the patient had anticonvulsant-induced hypocalcemia, and he carried that diagnosis for 18 years. Chromosome 22q11 deletion syndrome was first suspected at age 32 years. The diagnosis was confirmed by fluorescence in situ hybridization analysis. This case underscores the variable clinical presentation of this congenital form of hypoparathyroidism. Kousseff (1984) described 3 sibs with a syndrome of sacral meningocele, conotruncal cardiac defects, unilateral renal agenesis (in 1 sib), low-set and posteriorly angulated ears, retrognathia, and short neck with low posterior hairline. Kousseff (1984) suggested autosomal recessive inheritance. Toriello et al. (1985) reported a similar, isolated case and designated the disorder Kousseff syndrome. Forrester et al. (2002) restudied the family reported by Kousseff (1984) and identified a 22q11-q13 deletion in the proband, his deceased brother, and his father. The proband had spina bifida, shunted hydrocephalus, cleft palate, short stature, cognitive impairment, and the typical craniofacial features of velocardiofacial syndrome, including low-set and dysplastic ears, broad base of the nose, narrow alae nasi, and retrognathia. His brother had died at 2 weeks of age with myelomeningocele, hydrocephalus, transposition of the great vessels, and unilateral renal agenesis, and his sister had died at 22 days of age with myelomeningocele, truncus arteriosus, hypocalcemia, and autopsy findings of absent thymus and parathyroid glands, consistent with DiGeorge anomaly. Maclean et al. (2004) reported 2 unrelated patients with Kousseff syndrome, 1 with a 22q11.2 deletion and the other without. The first was a 4-year-old girl with a sacral myelomeningocele, tetralogy of Fallot, microcephaly, hydrocephalus, hypoplasia of the corpus callosum, and moderate developmental delay, who had a normal chromosome 22q11.2 FISH test and did not exhibit the facial phenotype of VCFS. The second patient, a male infant who died at 10 days of age, had a large sacral myelomeningocele, hydrocephalus, Arnold-Chiari malformation, atrial septal defect, conoventricular ventricular septal defect, type B interrupted aortic arch, hypocalcemia, and suspected duodenal stenosis; FISH testing revealed a 22q11.2 microdeletion. Maclean et al. (2004) concluded that Kousseff syndrome is a distinct clinical entity that is genetically heterogeneous. Kujat et al. (2006) reported that 5 (83%) of 6 patients with a 22q11.2 microdeletion had renal anomalies, including renal dysplasia, hydronephrosis, and unilateral renal agenesis. Robin et al. (2006) reviewed clinical data including brain imaging on 21 patients with polymicrogyria associated with deletion 22q11.2 and another 11 patients from the literature. The authors found that the cortical malformation consisted of perisylvian polymicrogyria of variable severity and frequent asymmetry with a striking predisposition for the right hemisphere (p = 0.008). Forbes et al. (2007) reported the ocular features of 90 consecutive patients with confirmed 22q11.2 deletion syndrome. Posterior embryotoxon was found in 49%, tortuous retinal vessels in 34%, eyelid hooding in 20%, strabismus in 18%, ptosis in 4%, amblyopia in 4%, and tilted optic nerves in 1%. Sundaram et al. (2007) described 2 patients with 22q11.2 deletion who had absent uterus and unilateral renal agenesis. One patient also had mild developmental delay, hypoparathyroidism, and psychiatric symptoms; the other patient also had high-arched palate, bulbous nasal tip, bicuspid aortic valve, short stature, and primary amenorrhea. Sundaram et al. (2007) suggested that mullerian or uterine/vaginal agenesis be included as part of the clinical spectrum of 22q11.2 deletion syndrome. Scheuerle (2008) reported a 14-year-old Latin American girl with 22q11.2 deletion syndrome who was found to have unilateral renal agenesis, uterine didelphys with duplication of the cervix, and imperforate vaginal hymen with hematometrocolpos. Binenbaum et al. (2008) reported 4 boys and 3 girls with 22q11.2 deletion syndrome, including 5 who had bilateral sclerocornea. Other eye findings included descemetocele in 5 eyes, microphthalmia in 1 eye, severe anterior segment dysgenesis in 1 eye, and bilateral iridocorneal adhesions in 1 patient. Binenbaum et al. (2008) suggested that a genetic locus at chromosome 22q11.2 may be involved in anterior segment embryogenesis, and that sclerocornea should be added to the clinical manifestations of the 22q11.2 deletion syndrome.
Patients with DiGeorge syndrome are hemizygous for the COMT gene (116790). In a study of 21 nonpsychotic DiGeorge syndrome patients aged 7 to 16 years, Shashi et al. (2006) found that those carrying the met allele of the ... Patients with DiGeorge syndrome are hemizygous for the COMT gene (116790). In a study of 21 nonpsychotic DiGeorge syndrome patients aged 7 to 16 years, Shashi et al. (2006) found that those carrying the met allele of the COMT V158M polymorphism (116790.0001), which results in increased dopamine in the prefrontal cortex, performed better on tests of general cognitive ability and on a specific test of prefrontal cognition compared to those with the val allele. Glaser et al. (2006) tested measures of executive function, IQ, and memory in 34 children and young adults with the 22q11.2 deletion syndrome (14 hemizygous for val158 and 30 for met158). No significant differences were detected between met- and val-hemizygous participants on measures of executive function. The groups did not differ on full-scale, performance, and verbal IQ or on verbal and visual memory. Glaser et al. (2006) suggested that either the COMT polymorphism has a small effect on executive function in 22q11.2 deletion syndrome or no effect exists at all.
Several expressed sequences have been identified in the region commonly deleted. Aubry et al. (1993) have identified a zinc finger gene ZNF74, Halford et al. (1993) reported the expressed sequence T10. The gene TUPLE1 (TUP-like enhancer of split ... Several expressed sequences have been identified in the region commonly deleted. Aubry et al. (1993) have identified a zinc finger gene ZNF74, Halford et al. (1993) reported the expressed sequence T10. The gene TUPLE1 (TUP-like enhancer of split gene-1; 600237) reported by Halford et al. (1993) is an attractive candidate for the central features of the syndrome. This putative transcription factor shows homology to the yeast transcription factor TUP, and to Drosophila enhancer of split. It contains 4 WD40 domains and shows evidence of expression at the critical period of development in the outflow tract of the heart and the neural crest derived aspects of the face and upper thorax. The gene localizes to the critical DiGeorge region but was not disrupted by the translocation breakpoint described by Augusseau et al. (1986). The possibility of this being a contiguous gene syndrome remains. Augusseau et al. (1986) described a patient (ADU) with 'partial' DGS. She had telecanthus, microretrognathia, severe aortic coarctation with hypoplastic left aortic arch, decreased E rosettes, and mild neonatal hypocalcemia. The apparently balanced translocation involved chromosomes 2 and 22: t(2;22)(q14;q11). The same translocation was present in her mother (VDU). The original paper reported that VDU had no features of DGS. However, Budarf et al. (1995) observed that subsequent publications cited VDU as mildly affected with hypernasal speech, micrognathia, and inverted T4/T8 ratio, which are all features seen in VCFS and DGS. The DGS phenotype in ADU, the VCFS phenotype in VDU, and a balanced translocation of chromosome 22 in both led Budarf et al. (1995) to clone the translocation, sequence the region containing the breakpoint, and analyze the DNA sequence for transcript identification. A gene disrupted by the rearrangement was identified. Their analysis suggested that there are at least 2 transcripts on opposite strands in the region of the t(2;22) breakpoint. The breakpoint disrupted a predicted ORF of one of these genes, deleting 11 nucleotides at the translocation junction. Additional fluorescence in situ hybridization studies and Southern blot analysis demonstrated that the deletions in chromosome 22 deletion-positive patients with DGS/VCFS include both of the transcripts at the t(2;22) breakpoint. Support that either of these putative genes is of significance in the etiology of DGS might come from determining whether all deleted patients are hemizygous for these loci and whether mutations in these genes are detectable in nondeletion patients with features of DGS. Lacking such evidence, the possibility remains that the translocation separates a locus control region from its target gene or produces a position effect. This has been suggested for the role of translocations seen in association with autosomal sex reversal and campomelic dysplasia (CMPD; 114290), where several disease-causing translocation breakpoints map 50 kb or more 5-prime of the SOX9 gene (608160). Bartsch et al. (2003) used cytogenetic and analyses to study a series of 295 patients with suspected DiGeorge/velocardiofacial syndrome. They identified 58 subjects with a 22q11 deletion, and none with a 10p deletion. The common deletion was present in 52 subjects, the proximal deletion in 5, and an atypical proximal deletion due to a 1;22 translocation in 1. Bartsch et al. (2003) suggested that intellectual and/or behavioral outcome may be better with the proximal versus the common 22q11 deletion. Demczuk et al. (1995) pointed to the existence of a strong tendency for 22q11.2 deletions in DGS, VCFS, and isolated conotruncal cardiac disease to be of maternal origin. With their experience of 22 cases in which parental origin could be determined, combined with recent results from the literature, 24 cases were found to be of maternal origin and 8 of paternal origin, yielding a probability of less than 0.01. Demczuk et al. (1995) reported the isolation and cloning of a gene encoding a potential adhesion receptor protein (600594) in the DGCR. They designated the gene DGCR2 and suggested DGCR1 as a symbol for the TUPLE1 gene. Pizzuti et al. (1996) described the cloning and tissue expression of a human homolog of the Drosophila 'dishevelled' gene (601225), a gene required for the establishment of fly embryonic segments. The 3-prime untranslated region of the gene was positioned within the DGS critical region and was found to be deleted in DGS patients. The authors stated that the gene may be involved in the pathogenesis of DGS. Demczuk et al. (1996) described the cloning of a gene, which they referred to as DGCR6 (601279), from the DGS critical region. The putative protein encoded by this gene shows homology with Drosophila melanogaster gonadal protein (gdl) and with the gamma-1 chain of human laminin (150290), which maps to chromosome 1q31. Edelmann et al. (1999) developed hamster-human somatic hybrid cell lines from VCFS/DGS patients and showed by use of haplotype analysis with a set of 16 ordered genetic markers on 22q11 that the breakpoints occurred within similar low copy repeats, designated LCR22s. Models were presented to explain how the LCR22s can mediate different homologous recombination events, thereby generating a number of rearrangements that are associated with congenital anomaly disorders. Shaikh et al. (2000) completed sequencing of the 3-Mb typically deleted region (TDR) and identified 4 LCRs within it. Although the LCRs differed in content and organization of shared modules, those modules that were common between them shared 97 to 98% sequence identity with one another. Sequence analysis of rearranged junction fragments from variant deletions in 3 DGS/VCFS patients implicated the LCRs directly in the formation of 22q11.2 deletions. FISH analysis of nonhuman primates suggested that the duplication events which generated the nest of LCRs may have occurred at least 20 to 25 million years ago. Stalmans et al. (2003) reported that absence of the 164-amino acid isoform of Vegf (Vegf164; see 192240), the only one that binds neuropilin-1 (602069), causes birth defects in mice reminiscent of those found in patients with deletion of 22q11. The close correlation of birth and vascular defects indicated that vascular dysgenesis may pathogenetically contribute to the birth defects. Vegf interacted with Tbx1, as Tbx1 expression was reduced in Vegf164-deficient embryos and knocked-down Vegf levels enhanced the pharyngeal arch artery defects induced by Tbx1 knockdown in zebrafish. Moreover, initial evidence suggested that a Vegf promoter haplotype was associated with an increased risk for cardiovascular birth defects in del22q11 individuals. Stalmans et al. (2003) concluded that genetic data in mouse, fish, and human indicated that VEGF is a modifier of cardiovascular birth defects in the del22q11 syndrome. Baldini (2002) reviewed the molecular basis of DiGeorge syndrome, with special emphasis on mouse models and the role of TBX1 in development of the pharyngeal arches. Yagi et al. (2003) screened for mutations in the coding sequence of TBX1 in 13 patients from 10 families who had the 22q11.2 syndrome phenotype but no detectable deletion in 22q11.2. They identified 3 mutations in TBX1 in 2 unrelated patients: 1 mutation was found in a case of sporadic conotruncal anomaly face syndrome/velocardiofacial syndrome and a second in a sporadic case of DiGeorge syndrome (602054.0002). A third mutation was found in 3 patients from a family with conotruncal anomaly face syndrome/velocardiofacial syndrome. The findings of Yagi et al. (2003) indicated that TBX1 mutations are responsible for 5 major phenotypes of the 22q11.2 syndrome, namely, abnormal facies (conotruncal anomaly face), cardiac defects, thymic hypoplasia, velopharyngeal insufficiency of the cleft palate, and parathyroid dysfunction with hypocalcemia; these mutations did not appear to be responsible for typical mental retardation that is commonly seen in patients with the deletion form of 22q11.2 syndrome. Saitta et al. (2004) traced the grandparental origin of regions flanking de novo 3-Mb deletions in 20 informative 3-generation families with DiGeorge or velocardiofacial syndromes. Haplotype reconstruction of the flanking regions showed an unexpectedly high number of proximal interchromosomal exchanges between homologs, occurring in 19 of 20 families, whereas the normal chromosome 22 in these probands showed interchromosomal exchanges in 2 of 15 informative meioses, a rate consistent with the genetic distance. Immunostaining with MLH1 antibody showed meiotic exchanges localized to the distal region of chromosome 22q in 75% of human spermatocytes tested, also reflecting the genetic map. There was no effect of proband gender or parental age on crossover frequency, and parental origin studies in 65 de novo 3-Mb deletions demonstrated no bias. Unlike Williams syndrome (194050), FISH analysis showed no chromosomal inversions flanked by LCRs in 22 sets of parents of 22q11-deleted patients or in 8 nondeleted patients with a DGS/VCFS phenotype. Saitta et al. (2004) concluded that significant aberrant interchromosomal exchange events during meiosis I in the proximal region of the affected chromosome 22 are the likely etiology for these deletions. Since this type of exchange occurs more often for 22q11 deletions than for deletions of 7q11, 15q11, 17p11, and 17q11, they suggested that there is a difference in the meiotic behavior of chromosome 22. Fernandez et al. (2005) found that 7 (13%) of 55 index patients with 22q11.2 deletion syndrome diagnosed by FISH analysis had inherited the deletion; 2 of the index patients were related as half sibs and had received the deletion from their shared mother. Using molecular techniques to characterize the size of the deletion, The authors found that 3 of 5 families had the smaller 1.5- to 2-Mb deletion and 2 families had the larger 3-Mb deletion; the size of the deletion in 1 family could not be determined. The findings suggested that small deletions may be more common in familial inheritance than larger deletions. Although the clinical severity did not differ between the 2 groups of patients, Fernandez et al. (2005) postulated that the smaller deletion may be associated with higher fecundity than the larger deletion. Paylor et al. (2006) identified a heterozygous 23-bp deletion in the TBX1 gene (602054.0004) in a mother and 2 sons with VCFS. The mother also had major depression (608516) and 1 of the sons was diagnosed with Asperger syndrome (see, e.g., 608638 and 209850). Paylor et al. (2006) suggested that the TBX1 gene is a candidate for psychiatric disease in patients with VCFS and DiGeorge syndrome. Kaminsky et al. (2011) presented the largest copy number variant case-control study to that time, comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing on recurrent deletions and duplications involving 14 copy number variant regions. Compared with controls, 14 deletions and 7 duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. The 22q11.2 deletion was identified in 93 cases and no controls for a p value of 9.15 x 10(-21) and a frequency in cases of 1 of 169.
A preliminary population study in the Northern region of England, which has a birth population of 40,000 per annum, revealed 9 cases born in 1993 with 22q11 deletions who presented with neonatal features. One of these was familial ... A preliminary population study in the Northern region of England, which has a birth population of 40,000 per annum, revealed 9 cases born in 1993 with 22q11 deletions who presented with neonatal features. One of these was familial with an asymptomatic carrier father. The overall birth prevalence appeared to be at least 1 in 4,000 (Burn et al., 1995). Goodship et al. (1998) presented prospective prevalence data derived from the same health region. Since approximately 75% of patients with 22q11 deletion have a cardiac abnormality, all infants with significant congenital heart disease born in 1994 and 1995 who were referred to the Northern (United Kingdom) Genetics Service were screened for 22q11 deletion. Significant congenital heart disease was defined as major structural malformation or disease requiring early invasive investigation or intervention. Additional cases born during this period without apparent heart malformation in whom a diagnosis of 22q11 deletion was made by a clinical geneticist were included. Among 69,129 live births there were 207 babies with significant congenital heart disease; fluorescence in situ hybridization analyses were performed in 170 of these. Five of these had 22q11 deletions. One baby with type B interruption of the aortic arch, ventricular septal defect, and 22q11 deletion was diagnosed at autopsy following sudden death at 11 days. Three further infants were diagnosed on the basis of a laryngeal web and hypocalcemia, dysmorphism, and dysmorphism with nasal voice, respectively. The minimum birth prevalence from these data was 13 per 100,000 live births, making 22q11 deletion the second most common cause of congenital heart disease after Down syndrome. Botto et al. (2003) identified 43 children with laboratory-confirmed 22q11.2 deletion among infants born in Atlanta, Georgia from 1994 to 1999. The overall prevalence was 1 in 5,950 births, with a prevalence of 1 in 6,000 to 1 in 6,5000 among whites, blacks, and Asians, and 1 in 3,800 among Hispanics. Most affected children (81%) had a heart defect, most commonly a conotruncal defect. Other common features included absent thymus (28%), central nervous system anomalies (12%), and renal anomalies (12%). Botto et al. (2003) estimated that at least 700 infants with 22q11.2 deletion syndrome are born annually in the United States.