22q11.2 recurrent (DGS/VCFS) region (proximal, A-B) (includes TBX1)

  • 3
    Haplo
    Score
  • 3
    Triplo
    Score

Region Facts

Region Name
22q11.2 recurrent (DGS/VCFS) region (proximal, A-B) (includes TBX1)
Cytoband
22q11.21
Genomic Coordinates
GRCh37/hg19 chr22:18912231-20287208 NCBI Ensembl UCSC
GRCh38/hg38 chr22:18924718-20299685 NCBI Ensembl UCSC

Dosage Sensitivity Summary (Region)

Dosage ID:
ISCA-37433
Curation Status:
Complete
Issue Type:
Dosage Curation - Region
Description:
The 22q proximal region contains a cluster of low copy repeats (LCRs) that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to nested CNVs involving recurrent breakpoints LCR A and LCR B. Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region.
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
Sufficient Evidence for Triplosensitivity (3)
Last Evaluated:
08/31/2018

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 20301696
    McDonald-McGinn, Emanuel and Zackai. GeneReviews: 22q11.2 Deletion Syndrome.
  • PUBMED: 27189754
    McDonald-McGinn et al. (2015) reviewed clinical findings in 22q11.2 deletion syndrome. See also PMID 21200182.
  • PUBMED: 26278718
    Burnside (2015) reviewed the literature and clinical findings of patients with recurrent 22q11.2 deletions, including proximal (A-B) region deletions. Of approximately 82,000 postnatal clinical encounters, a total of 35 A-B region deletions were detected; 8 had parental testing: 5 de novo, 2 maternally inherited, and one case with two affected siblings (parent of origin unknown). In relation to a reported increase in relative inheritance rate for the A-B deletion, “The reason(s) for the apparent differences… between the 2 deletion intervals remains to be determined conclusively.”
HI Evidence Comments:
Deletion of the 22q11.2 proximal (A-B) region is associated with DiGeorge/Velocardiofacial (DGS/VCFS) syndrome. Clinical findings are variable, but typically include congenital heart disease (particularly conotruncal malformations), palatal abnormalities (particularly velopharyngeal incompetence, cleft palate and bifid uvula), characteristic facial features, DD/ID, behavior problems, immune deficiency, and hypocalcemia. Most 22q11.2 (DGS/VCFS) deletions (>90 percent) are de novo. This deletion is enriched in the clinical population. Additional relevant literature is summarized below: Case-control studies: PMID 25217958: Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, deletions of the recurrent 22q11.2 (DGS/VCFS) A-B region were observed in 158/29,085 cases versus 0/19,584 controls (p=3.97E-36; LR: Inf, CI: 43.9 to Inf).

Triplosensitivity (TS) Score Details

TS Score:
3
TS Evidence Strength:
Sufficient Evidence for Triplosensitivity (Disclaimer)
TS Disease:
  • chromosome 22q11.2 microduplication syndrome Monarch
TS Published Evidence:
  • PUBMED: 20301749
    Firth. GeneReviews: 22q11.2 Duplication. Review of the phenotype associated with duplication of proximal 22q11.2. Similar to the reciprocal deletion, this review combines data from reports of patients with both A-D (3 Mb) and A-B (1.5 Mb) region duplications. The phenotype is described as, “…generally mild and highly variable; findings range from apparently normal to intellectual disability/learning disability, delayed psychomotor development, growth retardation, and/or hypotonia. The high frequency with which the 22q11.2 duplication is found in an apparently normal parent of a proband suggests that many individuals can harbor a duplication of 22q11.2 with no discernible phenotypic effect.”
  • PUBMED: 19254783
    Portnoi (2009) reviewed the literature and summarized findings from approximately 50 unrelated cases of duplications involving proximal 22q11.2. The author noted, “The phenotype of patients is extremely variable, ranging from multiple defects to mild learning difficulties, sharing features with DGS/VCFS, including heart defects, urogenital abnormalities, velopharyngeal insufficiency with or without cleft palate, and with some individuals being essentially normal.”
  • PUBMED: 18414210
    Ou et al. (2008) reviewed clinical findings of 22q11.2 CNV carriers from a cohort of 7000 clinical aCGH cases. The authors report two unrelated probands (Pts 4 and 5) and two relatives of patient 4 (sibling and father) with the nested A-B (1.5 Mb) duplication. Clinical findings in common in at least two carriers included speech delay, variable dysmorphic features, hypernasal speech and failure to thrive.
TS Evidence Comments:
Duplication of the 22q11.2 proximal (A-B) region is associated with a highly variable clinical phenotype, ranging from apparently normal to expression a broad range of clinical features, including nonspecific phenotypes (intellectual disability, learning disability, developmental delays, autism, psychiatric disorder growth delays, hypotonia) as well as phenotypes that overlap clinical findings of DGS/VCFS. 22q11.2 duplications are frequently inherited; incomplete penetrance has been demonstrated. This duplication is enriched in the clinical population. Additional relevant literature is summarized below: Case-control studies: PMID 25217958: Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, duplication of the recurrent 22q11.2 (DGS/VCFS) A-B region, the presumed critical region between LCR22A and -D, was observed in 97/29,085 cases versus 12/19,584 controls (p=1.35E-11; LR: 5.44, CI: 3.28 to 9.27). Cases and Case Series: PMID 17250668: Alberti et al. (2007) describe a patient referred for developmental delay at 7 months. At a follow up visit at age 2.5 years, she exhibited intellectual disability, motor delay, and mildly dysmorphic features. aCGH showed a 1.5 Mb proximal 22q duplication, which was confirmed by MLPA analysis. The duplication was on the maternal allele, but was de novo in origin. The authors note that her features were similar overall to those with larger 3 Mb duplications, confounding genotype-phenotype correlations. See also: PMID 27158440 (Wenger et al., 2016) PMID 28114601 (Hoeffding et al., 2017) PMID: 27108843 (Forbes et al., 2016) PMID: 25118001 (Dupont et al., 2015)

Genomic View

Select assembly: (NC_000022.10) ()