ClinGen Dosage Sensitivity Curation Page

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

  • Curation Status: Complete
  • id: ISCA-37446
  • Date last evaluated: 2018-08-31
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 3


Location Information

Select assembly: (NC_000022.10) ()
Evidence for haploinsufficiency phenotype
PubMed ID Description
20301696 McDonald-McGinn, Emanuel and Zackai. GeneReviews: 22q11.2 Deletion Syndrome.
27189754 McDonald-McGinn et al. (2015) reviewed clinical findings in 22q11.2 deletion syndrome. See also PMID 21200182.
Burnside (2015) reviewed the literature and clinical findings of patients with recurrent 22q11.2 deletions, including proximal (A-D) region deletions.

Haploinsufficiency phenotype comments:

Deletion of the 22q11.2 proximal (A-D) 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. *The 22q11.2 region contains a cluster of low copy repeats (LCRs) that mediate recurrent copy number changes through non-allelic homologous recombination. Proximal 22q11.2 rearrangements involve the centromeric LCR22A and either LCR22B (A-B, approximate size 1.5 Mb) or LCR22D (A-D, approximate size 3.0 Mb) (note in some literature these LCRs are referred to as LCR22-2, 3a and -4, respectively). This review refers to patients with the most common A-D rearrangement, observed in approximately 85-90 percent of cases. The phenotypes in individuals with A-B and A-D deletions are largely indistinguishable. Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region. 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, deletion of the recurrent 22q11.2 (DGS/VCFS) A-B region, the presumed critical region between LCR22A and -D, was observed in 158/29,085 cases versus 0/19,584 controls (p=3.97E-36; LR: Inf, CI: 43.9 to Inf).

Evidence for triplosensitivity phenotype
PubMed ID Description
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.?
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.?
18414210 Ou et al. (2008) reviewed clinical findings of 22q11.2 CNV carriers from a cohort of 7000 clinical aCGH cases. Three probands (Pts 1-3) and two relatives of patient 1 (sibling and mother) with A-D (3 Mb) region duplications were reported. Clinical findings in common in at least two carriers included developmental delay, speech delay, variable dysmorphic features, hypernasal speech, hearing impairment, and behavioral abnormalities. Parental samples were unavailable for patients 2 and 3.

Triplosensitivity phenotype comment:

Duplication of the 22q11.2 proximal (A-D) 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. *The 22q11.2 region contains a cluster of low copy repeats (LCRs) that mediate recurrent copy number changes through non-allelic homologous recombination. Proximal 22q11.2 rearrangements involve the centromeric LCR22A and either LCR22B (A-B, approximate size 1.5 Mb) or LCR22D (A-D, approximate size 3.0 Mb) (note in some literature these LCRs are referred to as LCR22-2, 3a and -4, respectively). This review refers to patients with the more common A-D rearrangement. The phenotypes in individuals with A-B and A-D duplications are largely indistinguishable. Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region. 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). 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)