Chromosome 22q11.2 Duplication Syndrome

A number sign (#) is used with this entry because of evidence that the phenotype results from a chromosome 22q11.2 microduplication involving multiple genes.

The duplication involves the same region as that deleted in DiGeorge syndrome (DGS; 188400) and velocardiofacial syndrome (VCFS; 192430).

Clinical Features

Edelmann et al. (1999) described a 4-year-old girl with failure to thrive, marked hypotonia, sleep apnea, and seizure-like episodes in infancy, who later showed delay of gross motor development with poor fine motor skills, velopharyngeal insufficiency, and a significant delay in language skills. Her facial features were mildly dysmorphic, with a narrow face and downslanting palpebral fissures. Hearing and vision were normal, and there were no detectable cardiac abnormalities. FISH analysis identified a partial interstitial duplication of chromosome 22q11, and haplotype analysis revealed that the unaffected mother and grandmother, who both had a history of preauricular ear pits, also carried the duplication. The duplication corresponded to the same 3-Mb region that is deleted in DiGeorge/velocardiofacial syndrome patients. Edelmann et al. (1999) stated that this was the first report of an interstitial duplication of the 3-Mb region in 22q11, excluding other parts of chromosome 22.

In the study of Ensenauer et al. (2003), the patients' phenotypes ranged from mild to severe, sharing a tendency for velopharyngeal insufficiency with DGS/VCFS but having other distinctive characteristics, as well. Although this series of patients was ascertained because of some overlapping features with DG/VCF syndromes, microduplication of 22q11.2 was considered to be a new syndrome by Ensenauer et al. (2003). The patients had been referred in the first instance for probing of the TUPLE1 gene (600237), which in no instance was found to be deleted.

The distinctive facial characteristics observed in more than half of the patients studied by Ensenauer et al. (2003) were superior placement of the eyebrows and widely spaced eyes with downslanting palpebral fissures. Two affected sisters were included in the series; both had learning disabilities, whereas one had cleft palate and the other poor growth. The affected mother also had learning problems. She had a kidney anomaly requiring surgery in childhood.

Yobb et al. (2005) showed that the phenotype of patients with 22q11.2 microduplications is exceedingly diverse, ranging from normal to behavioral abnormalities to multiple defects, only some of which are reminiscent of the 22q11.2 deletion syndrome. This diversity makes ascertainment difficult and indicated the necessity for a rapid-screening method. Yobb et al. (2005) demonstrated the utility of 4 different screening methods. They also reported the first patient with a 22q11.2 triplication and showed that the patient's mother carried a 22q11.2 microduplication. Yobb et al. (2005) strongly recommended that relatives of patients with 22q11.2 microduplications be tested, since they found several phenotypically normal parents who were carriers of the chromosomal abnormality.

De La Rochebrochard et al. (2006) reported a 22-week female fetus with lethal congenital nonconotruncal complex heart defects, including single atrium, small left ventricle, large right ventricle, double outlet right ventricle with transposed great arteries, persistent left superior vena cava, and total anomalous pulmonary venous return. Other features included abdominal situs inversus totalis with normal cardiac situs, and thoracic heterotaxia with right predominance and bilateral trilobed lungs. She also had facial dysmorphic features. FISH and PCR analysis identified a 3-Mb duplication of 22q11.2 inherited from the father, who was clinically unaffected but had a mildly decreased IQ. A fetus in a subsequent pregnancy was also found to carry the duplication, but no abnormalities were detected on prenatal ultrasound or at birth. De La Rochebrochard et al. (2006) emphasized the phenotypic variability of the duplication in this family.

Courtens et al. (2008) reported 2 unrelated families with 22q11.2 microduplication. In 1 family, the proband had psychomotor retardation, behavioral problems, increased height and weight, and mild dysmorphic features. His brother and father, who also had the microduplication, had a similar phenotype. In contrast, 2 carriers from a second family were completely normal with high intellect, whereas the proband had mild learning difficulties and mild facial dysmorphism. Courtens et al. (2008) noted that the delineation of a 22q11.2 microduplication 'syndrome' may be due to ascertainment bias when seeking microdeletions of this region, and suggested that 22q11.2 microduplication could be either a nonpathogenic polymorphism or a syndrome with reduced penetrance.

Yu et al. (2008) studied 2 families with 22q11.2 microduplications. The first family had 8 individuals over 3 generations who carried a 3-Mb duplication and showed intrafamilial phenotypic variation including heart defect, submucous cleft, intellectual disability, speech delay, behavior problems, and brachydactyly. In the second family, a 1.5-Mb duplication was detected in a neonate and her normal mother. The neonate presented with laryngomalacia and stridor, and cranial ultrasound showed small subependymal cysts bilaterally; there was no heart defect or cleft palate and chest x-ray, and renal ultrasound were normal. Review at 2 months of age showed normal growth and development.

Wentzel et al. (2008) reported 2 unrelated families segregating chromosome 22q11.2 duplication. In 1 family, the 3-year-old proband showed delayed psychomotor development with poor speech acquisition. Dysmorphic features included full lips, epicanthal folds, flat nasal bridge, prognathism, thick ear helices, high-arched palate, and muscular hypotonia. Array CGH and multiplex ligation-dependent probe amplification (MLPA) analysis identified a 2.09 to 3.06-Mb duplication at chromosome 22q11.21, which was also detected in the mother, maternal grandmother, and maternal uncle. The proband's relatives were unaffected, except for very mild possible manifestations in the mother, who had nasal speech and dyslexia. The 3-year-old proband of the second family was mentally retarded with delayed language development. Dysmorphic features included microcephaly, square-shaped head with large prominent forehead, slight hypertelorism, ptosis, epicanthal folds, and a flat nose. He also had a high-arched palate, low-set ears with thick helices, deviant facial expressions, muscular hypotonia, and nasal speech. MPLA analysis showed the same 22q11.21 duplication as observed in the first family. The duplication was also found in the patient's father, who had borderline mental retardation/learning disabilities, and in a younger brother who was born prematurely and died from gastrointestinal bleeding at age 30 weeks. Neither proband had cardiac malformations. Wentzel et al. (2008) emphasized the intrafamilial phenotypic variability of the 22q11.2 duplication syndrome.

Wentzel et al. (2008) reviewed the clinical features of 36 published cases of the 22q11.2 duplication syndrome. The most frequently reported features were mental retardation/learning difficulties, deficits in memory performance, perceptual organization, and verbal comprehension, ADHD, and speech impairment (97%). Other characteristics included delayed psychomotor development (67%), growth retardation (63%), and muscular hypotonia (43%). The most common dysmorphic features were hypertelorism (70%), broad flat nose (53%), micrognathia (52%), velopharyngeal insufficiency (48%), dysplastic ears (45%), epicanthal folds (42%), and downslanting palpebral fissures (41%). Congenital heart malformation, visual and hearing impairment, seizures, microcephaly, ptosis, and urogenital abnormalities have also been reported. However, overall, the 22q11.2 duplication syndrome phenotype ranged from no abnormality or mild learning disabilities to severe mental retardation with multiple congenital malformations. Wentzel et al. (2008) noted that, although it is possible to perform prenatal testing, it is impossible to predict the phenotypic outcome of a 22q11.2 duplication.

Cytogenetics

DiGeorge/velocardiofacial syndrome is a common disorder resulting from microdeletion in band 22q11.2 resulting from misalignment of low-copy repeats (LCRs). Although both deletion and duplication are expected to occur in equal proportions as reciprocal events caused by LCR-mediated rearrangements, very few microduplications have been identified. Ensenauer et al. (2003) identified 13 cases of 22q11.2 microduplication, primarily by interphase FISH, out of 653 patients referred for testing. The size of the duplications, determined by FISH probes from bacterial artificial chromosomes (BACs) and P1 artificial chromosomes (PAC), range from 3.4 Mb to 6 Mb, and the exchange points seem to involve an LCR. Molecular analysis based on 15 short tandem repeats confirmed the size of the duplications and indicated that at least 1 of 15 loci had triplication.

Cotter et al. (2005) screened 372 patients referred for DGS/VCFS testing and identified 30 patients with 22q11.2 deletion. No patients were identified with the 22q11.2 microduplication by interphase FISH. They suggested that screening a more diverse patient population, as well as normal individuals, would better characterize the frequency and phenotype of 22q11.2 microduplication syndrome.

Brunet et al. (2006) studied 295 patients with widely variable manifestations associated with DGS/VCFS and identified 12 patients who carried a 22q11.2 deletion, but no patients with 22q11.2 microduplication were identified. The authors suggested that this is a rare event in patients with DGS/VCFS features.

To investigate large copy number variants (CNVs) segregating at rare frequencies (0.1 to 1.0%) in the general population as candidate neurologic disease loci, Itsara et al. (2009) compared large CNVs found in their study of 2,500 individuals with published data from affected individuals in 9 genomewide studies of schizophrenia, autism, and mental retardation. They found evidence to support the association of duplication at chromosome 22q11.2 with autism and schizophrenia (CNV P = 0.330). They identified 31 duplications in this region; 9 of these were disease-associated. Much stronger evidence was obtained for association of deletion in this region with neurologic disorders (see 600850).

Sahoo et al. (2011) analyzed 38,779 individuals referred to the diagnostic laboratory for microarray testing for the presence of copy number variants encompassing 20 putative schizophrenia susceptibility loci. They also analyzed the indications for study for individuals with copy number variants overlapping those found in 6 individuals referred for schizophrenia. After excluding larger gains or losses that encompassed additional genes outside the candidate loci (e.g., whole-arm gains/losses), Sahoo et al. (2011) identified 1,113 individuals with copy number variants encompassing schizophrenia susceptibility loci and 37 individuals with copy number variants overlapping those present in the 6 individuals referred for schizophrenia. Of these, 1,035 had a copy number variant of 1 of 6 recurrent loci: 1q21.1 (612474, 612475), 15q11.2 (608636), 15q13.3 (612001), 16p11.2 (611913), 16p13.11 (610543, 613458), and 22q11.2 (192430). The indications for study for these 1,150 individuals were diverse and included developmental delay, intellectual disability, autism spectrum, and multiple congenital anomalies. Sahoo et al. (2011) identified the 22q11.2 microduplication in 94 individuals; 10 were de novo, 21 maternally inherited, 12 paternally inherited, and 51 of unknown inheritance. The average age at diagnosis was 9.2 years with an age range of 0.8 to 43.3 years, and the indications for study included multiple congenital anomalies, congenital heart defect, failure to thrive, autism, hypocalcemia, seizure disorder, postaxial polydactyly, and clubfeet. This duplication was seen in 63 of 23,250 cases referred to their laboratory for a frequency of 0.27% and not at all in 5,674 controls, for a p value of less than 0.001 (see Itsara et al., 2009). Sahoo et al. (2011) concluded that the results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and imply the existence of shared biologic pathways among multiple neurodevelopmental conditions.

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 duplication was identified in 32 cases and 5 controls for a p value of 0.0011 and a frequency of 1 in 492 cases.

Animal Model

Suzuki et al. (2009) determined the developmental impact of overexpression of an approximately 190-kb segment of human chromosome 22q11.2, which includes the genes TXNRD2 (606448), COMT (116790), and ARVCF (602269), on behaviors in bacterial artificial chromosome (BAC) transgenic mice. BAC transgenic mice and wildtype mice were tested for their cognitive capacities, affect- and stress-related behaviors, and motor activity at 1 and 2 months of age. BAC transgenic mice approached a rewarded goal faster (i.e., incentive learning), but were impaired in delayed rewarded alternation during development. In contrast, BAC transgenic and wildtype mice were indistinguishable in rewarded alternation without delays, spontaneous alternation, prepulse inhibition, social interaction, anxiety-, stress-, and fear-related behaviors, and motor activity. Compared with wildtype mice, BAC transgenic mice had a 2-fold higher level of COMT activity in the prefrontal cortex, striatum, and hippocampus. Suzuki et al. (2009) suggested that overexpression of this 22q11.2 segment may enhance incentive learning and impair the prolonged maintenance of working memory, but has no apparent affect on working memory per se, affect- and stress-related behaviors, or motor capacity. High copy numbers of this 22q11.2 segment may contribute to a highly selective set of phenotypes in learning and cognition during development.