ClinGen Dosage Sensitivity Curation Page

22q11.2 recurrent region (distal type I, D-E/F)

  • Curation Status: Complete
  • id: ISCA-37397
  • Date last evaluated: 2015-03-12
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 3


Location Information

  • 22q11.21-q11.22
  • GRCh37/hg19 chr22: 21,917,117-23,649,111
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr22: 21,562,828-23,306,924
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000022.10) ()
Evidence for haploinsufficiency phenotype
PubMed ID Description
23765049 Mikhail et al. (2014) reported 13 unrelated patients with 22q11.2 distal deletions and compared clinical findings with those of previously reported cases to correlate phenotypes with deletion size and position. Three of the 13 patients in their cohort carried the larger ~1.8 Mb deletions flanked by LCR22-D and -F. These deletions were associated with a variable clinical phenotype that may include preterm birth, pre- and/or postnatal growth restriction, DD/ID, behavioral problems, cardiovascular defects, skeletal anomalies and mild dysmorphic facial features. Six patients with ~1.1 Mb deletions flanked by LCR22-D and ?E had similar overlapping features to patients with the larger ~1.8 Mb deletions involving LCR22-D to F. The authors proposed 22q11.2 distal deletions may be classified into three distinct clinical entities: type I: with deletions flanked by LCR22-D and either -E or -F; type II: with deletions flanked by LCR22-E and -F; and type III: with any deletion in this region minimally spanning the LCR22-F to -G interval and encompassing the SMARCB1 gene.
21671380 Tan et al. (2011) reported a patient (Patient 1) with a de novo LCR22-D to -E deletion who had growth and developmental delays, craniofacial dysmorphisms, and MCA: cardiac, skeletal and urogenital anomalies; and reviewed the clinical findings of patients with similar deletions in the literature.
18179902 Ben-Shachar et al. (2008) reported six unrelated patients with de novo 1.4 Mb or 2.1 Mb 22q11.2 distal deletions extending from LCR22-4 (-D) to either LCR22-5 (-E) or LCR22-6 (-F), respectively. Four patients with deletions from LCR22-4 to LCR22-5 presented with developmental delay, dysmorphic facial features, prematurity, prenatal and postnatal growth restriction, and mild skeletal dysplasia. Two patients with 1.4 Mb deletions flanked by LCR22-4 and LCR22-6 displayed cleft palate and high arched palate in addition to the clinical features observed in the patients with 2.1 Mb deletions of the LCR22-4 to LCR22-5 region. Two patients were found to have cardiac defects: one with a 2.1 Mb deletion had truncus arteriosus, and another with a 1.4 Mb deletion had a bicuspid aortic valve.

Haploinsufficiency phenotype comments:

Distal 22q11.2 deletions are caused by rearrangements involving the more telomeric low copy repeat (LCR) regions in 22q11.2, LCR22-D, -E, -F, -G and -H (note, in some literature, these LCRs are referred to as LCR22-4, -5, -6, -7, and -8 respectively). This review refers to patients with deletions extending from LCR22-D to either LCR22-E or -F. Patients with deletions involving this region present with a variable clinical phenotype that may include preterm birth, pre- and/or postnatal growth restriction, DD/ID, behavioral problems, cardiovascular defects, skeletal anomalies and mild dysmorphic facial features. The region from LCR22-D to -E appears to be critical for expression of these phenotypes, therefore patients with either LCR22-D to -E or -D to -F deletions are grouped together. The majority of deletions affecting this region are de novo. In addition, a large-scale case-control comparison study has shown enrichment of distal 22q11.2 deletions within the clinical population (see Coe et al., 2014 (PMID 25217958), Cooper et al., 2011 (PMID 21841781)). For a review of patients with deletions of the LCR22-E to -F region, see linked issue. NOTE: these deletions are distinct from, and do not include the deleted region causative for DiGeorge/Velocardiofacial syndrome, which involves the centromeric (proximal) LCRs, LCR22-A to D.

  • Triplosensitivity score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
22140377 Wincent et al. (2011) reported 16 patients with distal 22q11.2 microduplications and reviewed the clinical findings of patients from previously reported studies. Three of 16 patients had maternally inherited duplications of the LCR22-D to -F and two patients had duplications from LCR22-D to -E (one maternally inherited and the other of unknown origin). These patients had a variable clinical phenotype that included mild to severe developmental delay. Two carrier parents were clinically unaffected, suggestive of incomplete penetrance.
19193630 Coppinger et al. (2009) identified 18 patients with idiopathic intellectual disability and/or congenital anomalies, who had distal 22q11.2 microduplications. Two patients (patients 10 and 17) had duplications from LCR22-D to -F, one was de novo and the other of unknown origin. Additional phenotypic information was only available for the patient with de novo duplication (Patient 10). This individual had normal development at age 1 year 8 months, optic disc coloboma and mild dysmorphic features.
18414210 Ou et al. (2008) reported two patients with distal 22q11.2 microduplications: one patient carried a ~1.1 Mb duplication from LCR22-D to -E had DD and mild facial dysmorphisms; the second patient had a ~1.8 Mb duplication from LCR22-D to -F and had MCA and facial dysmorphisms, however the associated causality of this duplication was uncertain.

Triplosensitivity phenotype comment:

Distal 22q11.2 duplications are caused by rearrangements involving the more telomeric low copy repeat (LCR) regions in 22q11.2, LCR22-D, -E, -F, -G and -H (note, in some literature, these LCRs are referred to as LCR22-4, -5, -6, -7, and -8 respectively). This review refers to patients with duplications extending from LCR22-D to either LCR22-E or -F. Patients with duplications involving this region present with a variable clinical phenotype that may include developmental delays and facial dysmorphisms. Incomplete penetrance has been reported. In addition, a large-scale case-control comparison study has shown enrichment of distal 22q11.2 duplications within the clinical population (see Coe et al., 2014 (PMID 25217958), Cooper et al., 2011 (PMID 21841781)). For a review of patients with duplications of the LCR22-E to -F region, see linked issue. NOTE: these duplications are distinct from, and do not include the duplicated region associated with the proximal 22q11.2 duplication syndrome, which involves the centromeric (proximal) LCRs, LCR22-A to D