Chromosome 22q11.2 Deletion Syndrome, Distal

A number sign (#) is used with this entry because of evidence that the 22q11.2 distal deletion syndrome appears to be a recurrent genomic disorder distinct from DiGeorge syndrome (DGS; 188400) and velocardiofacial syndrome (VCFS; 192430).

Clinical Features

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.

Using CGH, Mikhail et al. (2014) identified 13 unrelated patients with variable size deletions in the distal 22q11.2 region. Six patients had the 1.1-Mb deletion flanked by LCR22-D and -E, and presented clinically with a phenotype consistent with previously reported cases with distal 22q11.2 microdeletions. Three patients had the 1.8-Mb deletion flanked by LCR22-D and -F and presented with a similar phenotype. Four patients had the 700-kb deletion flanked by LCR22-E and -F and presented with a milder phenotype that lacked growth restriction and cardiovascular defects. Patients with larger deletions presented with preterm birth, with the gestational age ranging from 27 to 36 weeks. Regardless of deletion size, all had global developmental delay and intellectual disability with a significant language delay component. Congenital cardiovascular defects were observed in 56% of patients with larger microdeletions and included septal defects, patent ductus arteriosus (PDA; 607411), bicuspid aortic valve, and cardiac dextrorotation. None of the 4 patients with the 700-kb LCR22-E and -F deletion had cardiac defect. The authors proposed categorizing distal 22q11.2 microdeletions into 3 genomic types: type 1 for deletions flanked by LCR22-D and either -E or -F; type 2 for deletions flanked by LCR22-E and -F; and type 3 for any deletion in this region minimally spanning the LCR22-F to -G intervals and encompassing the SMARCB1 gene (601607). All 3 types are pathogenic and are most often de novo. The type 2 deletion seems to be relatively less frequent and to have a milder phenotype less likely to include preterm birth, pre- and postnatal growth restriction, and cardiovascular defects, whereas the type 3 deletion is characterized by a very high incidence of malignant rhabdoid tumors in infancy and early childhood.

Cytogenetics

In northeastern Finnish genetic isolates, Stoll et al. (2013) found an association between a founder 240-kb deletion of chromosome 22q11.22 encompassing the TOP3B gene (603582) and schizophrenia (odds ratio (OR) of 1.84, p less than 0.03) as well as cognitive impairment (OR of 4.6, p = 0.03). The cohorts included several hundreds of patients and thousands of controls. Four individuals were homozygous for the deletion; all 4 had cognitive impairment and 2 had schizophrenia. The 22q11.22 deletion lies in the 1.4- to 2.1-Mb distal 22q11.2 microdeletion syndrome region. Stoll et al. (2013) found that TOP3B interacted with FMRP (FMR1; 309550), which is mutated in fragile X syndrome (300624). Stoll et al. (2013) suggested that loss of TOP3B is involved in neurodevelopmental disorders.

In a 12-year-old girl with cognitive impairment and multiple behavioral abnormalities, including autistic features, ADHD, oppositional defiant disorder, and suspected psychosis, Kaufman et al. (2016) identified a heterozygous 268-kb deletion of chromosome 22q11.22 encompassing the TOP3B gene. She also had mild dysmorphic craniofacial features. The family history reportedly contained significant behavioral, psychiatric, and cognitive deficits on both the maternal and paternal sides. However, no family members were available for evaluation or genetic studies. It was therefore not clear if the deletion occurred de novo or was inherited, or if other genetic variants were present. Studies of patient cells were not performed.