ClinGen Dosage Sensitivity Curation Page

22q11.2 recurrent region (central, B/C-D) (includes CRKL)

  • Curation Status: Complete
  • id: ISCA-37516
  • Date last evaluated: 2017-09-14
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 2
  • ClinGen Triplosensitivity Score: 1


Location Information

Select assembly: (NC_000022.10) ()
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
25123976 Rump et al., (2014) report 10 novel 22q11.21 deletions involving the LCR22-B/C to LCR22-D region (6 LCR22-B-D and 4 LCR22-C-D). These deletions were identified in 24 total individuals (12 LCR22-B-D and 12 LCR22-C-D). The clinical features observed in these patients are variable and include developmental delay, behavioral problems, dysmorphic facial features, growth delay, skeletal/digital abnormalities, congenital heart anomalies, renal abnormalities, genital anomalies, ear infections, and additional less common features. Parental testing was performed in 9 of the reported families, with 8/9 probands inheriting the deletion from a parent. Of note, this study also reported 3 additional deletions that involved LCR22C but had distal breakpoints that were beyond LCR22D. These deletions were found to have a more severe clinical presentation that included a higher percentage of patients with cardiac anomalies and growth restriction. Parental studies revealed that each of these three deletions represented a de novo event.
22893440 Verhagen et al., (2012) report 5 novel 22q11.21 deletions involving the LCR22-B/C to LCR22-D region (1 LCR22-B-D and 4 LCR22-C-D). These deletions were identified in 8 total individuals (2 LCR22-B-D and 6 LCR22-C-D). The clinical features observed in these patients are variable and include developmental delay, behavioral and/or psychiatric problems, dysmorphic facial features, microcephaly, congenital heart defects, genital anomalies, as well as additional less common features. Parental testing was performed in 4 of the reported families, with 3/4 probands inheriting the deletion from a parent.
26278718 Burnside (2015) reviews the clinical findings previously reported in association with LCR22-B/C to LCR22-D (central) deletions and also reports on an additional 23 patients. The clinical features described in these patients are highly variable with the most common features including growth retardation, immune deficiency/recurrent infections, CNS anomalies/seizures, developmental delay, intellectual disability, skeletal anomalies, cardiovascular defects, psychiatric/behavioral problems, genitourinary anomalies, and dysmorphic features. Parental testing was performed in 7 of the novel patients reported in this study, with four of the deletions being de novo, 2 being inherited, and one unknown.

Haploinsufficiency phenotype comments:

Central 22q11.2 deletions are caused by rearrangements involving the centrally-located low copy repeat (LCR) regions in 22q11.2, LCR22-B, -C, and -D (note, in some literature, these LCRs are referred to as LCR22-3a, -3c, and -4, respectively). This review refers to patients with deletions extending from either LCR22-B to -D (~740 kb) or LCR22-C to -D (~375 kb). NOTE: this region is nested at the distal end of the larger ~3 Mb LCR22-A to -D interval associated with DiGeorge syndrome (DGS), but does not include DGS critical genes HIRA or TBX1. Evidence is emerging that deletion of this region is associated with a variable clinical phenotype that may include: dysmorphic facial features, growth restriction/short stature, CNS anomalies/seizures, developmental delay (including language delay), intellectual disability, psychiatric/behavioral problems, skeletal anomalies, cardiovascular defects, genitourinary anomalies, and immune deficiency/recurrent infections. Parental testing has shown 21/35 (60%) deletions represent de novo events. Due to phenotypic variability, incomplete penetrance, and lack of case-control data, the current haploinsufficiency score for this region is a 2.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
22796526 Pebrel-Richard et al., (2012) present a single patient with a duplication between LCR22-B and LCR22-D. The clinical features reported in the proband include muscular hypotonia, developmental delay (speech and motor), and mild dysmorphic facial features. Parental testing was performed, and this duplication was found to be inherited from the proband?s mother.
18414210 Ou et al., (2008) present a single patient with a duplication between LCR22-B and LCR22-D. The clinical features observed in this patient included severely undervirilized external genitalia with hypospadias and cryptorchidism. Parental testing was performed, and this duplication was found to be inherited from the proband?s phenotypically normal father.
19490635 Fern?ndez et al., (2009) present a single patient with a duplication between LCR22-C and LCR22-D. The clinical features observed in this patient included complete cleft palate and upslanting palpebral fissures, with normal development at 13 months of age. Parental testing was performed, and this duplication was found to be inherited from the proband?s mother. Of note this duplication was also found in the proband's maternal uncle, two maternal aunts, and the maternal grandfather, all of whom were reported to be normal.

Triplosensitivity phenotype comment:

Central 22q11.2 duplications are caused by rearrangements involving the centrally-located low copy repeat (LCR) regions in 22q11.2, LCR22-B, -C, and -D (note, in some literature, these LCRs are referred to as LCR22-3a, -3c, and -4, respectively). This review refers to patients with duplications extending from either LCR22-B to -D (~740 kb) or LCR22-C to -D (~375 kb). NOTE: this region is nested at the distal end of the larger ~3 Mb LCR22-A to -D interval associated with DiGeorge syndrome (DGS), but does not include DGS critical genes HIRA or TBX1. Due to a limited number of patients reported in the literature, phenotypic variability, incomplete penetrance and lack of case-control data, the current triplosensitivity score for this region is 1.