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22q11.2 recurrent region (distal type I, D-E/F) |
- 3
Haplo
Score - 1
Triplo
Score
Dosage Sensitivity Summary (Region)
Dosage ID:
ISCA-37397
Curation Status:
Complete
Issue Type:
Dosage Curation -
Region
Description:
The 22q11.2 region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to distal region CNVs involving recurrent breakpoints LCR22-D and LCR22-E or -F, often referred to in the literature as the distal type I region.
Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region.
NOTE: Curation of overlapping CNVs involving the LCR22-E to -F (distal type II) or LCR22-D to G/H and LCR22-E/F to -H (distal type III) regions are linked below.
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency
(3)
Triplosensitivity:
Little Evidence for Triplosensitivity
(1)
Related Links:
Last Evaluated:
12/08/2022
Haploinsufficiency (HI) Score Details
HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency
(Disclaimer)
HI Disease:
- chromosome 22q11.2 deletion syndrome, distal Monarch
HI Evidence:
-
PUBMED:
23765049
Mikhail et al. (2014) identified 9 unrelated patients with 22q11.2 D-E (6) or D-F (3) deletions from a large cohort of patients referred for clinical microarray testing and summarized previously reported cases. All individuals presented with variable neurodevelopmental phenotypes including developmental delay and intellectual disability. Additional findings included pre- and/or postnatal growth restriction in 7 individuals, 6 had heart findings, and 4 had microcephaly and seizures. Inheritance was de novo in 4 cases, negative for one parent in 3 cases, and unknown in 2 cases.
-
PUBMED:
30524331
Oliveira et al. (2019) reviewed the literature for cases of 22q11.2 D-E deletions. A total of 33 individuals were reported across 15 studies, with the common phenotypic findings including congenital heart disease (truncus arteriosus was the most common), prematurity and low birth weight, language development delay, bone malformations, facial dysmorphisms, and a wide range of intellectual disability. Inheritance information was not summarized.
-
PUBMED:
26141236
Digilio et al. (2015) reviewed the literature with a focus on heart defects associated with distal deletions of 22q11.2. Primary resources and the DECIPHER database were used to identify 12 individuals with 22q11.2 D-E (referred to as LCR22-4 to -5), and 7 individuals with 22q11.2 D-F (referred to as LCR22-4 to -6) deletions. The authors concluded that the spectrum of congenital heart defects in 22q11.2 distal deletions is wider than originally considered, and includes left ventricular non-compaction cardiomyopathy with aortic valve anomalies, truncus arteriosus, bicuspid aortic valve, as well as VSD, ASD, and PDA. Inheritance information was not summarized.
-
PUBMED:
18179902
Ben-Shachar et al. (2008) reported 6 unrelated patients with de novo 22q11.2 D-E or D-F deletions (referred to as LCR22-4 to -5 and LCR22-4 to -6, respectively) identified by clinical array-based testing. A total of 4 patients had D-E deletions and presented with developmental delay, dysmorphic facial features, prematurity, prenatal and postnatal growth restriction, and mild skeletal dysplasia. The 2 patients with D-F deletions displayed cleft palate and high arched palate in addition to the clinical features observed in the patients with D-E region deletions. Cardiac defects were seen in 2 patients: one with truncus arteriosus and another with a bicuspid aortic valve.
HI Evidence Comments:
Deletion of the 22q11.2 D-E/F region is associated with a variable clinical phenotype that may include preterm birth, pre- and/or postnatal growth restriction, developmental delay/intellectual disability, behavioral problems, cardiovascular defects, skeletal anomalies and mild dysmorphic facial features. The D-E region appears to be critical for expression of these phenotypes, therefore patients with either D-E or D-F deletions are summarized. The majority of deletions affecting this region are de novo, although inheritance from an affected parent has been reported. Case-control comparison studies have shown enrichment of this deletion in clinical populations. Therefore, the haploinsufficiency score is 3.
Additional relevant literature is summarized below:
Case-Control Studies:
PMID: 25217958
Coe et al. (2014) performed a large-scale case-control comparison study of the relative prevalence of CNVs in children with developmental delay/intellectual disability, multiple congenital anomalies, and other developmental phenotypes compared to controls. Deletions of the 22q11.2 distal D-E/F region was observed in 20/29,085 cases versus 0/19,584 controls (p=1.25 E-05; LR: Inf, 95% CI: 5.05-Inf), demonstrating enrichment of this CNV in the clinical population. See also Cooper et al. (2011) PMID 21841781, which uses an overlapping (older) dataset.
Reports of distal type I deletions defined as and/or including the C-E region:
PMID: 26278718
Burnside (2015) reviewed clinical findings of distal type I deletions, defined as C-E, D-E, or D-F deletions, including a phenotypic description of 2 fetuses and summary of 45 additional postnatal patients from the literature. Clinical features amongst the previously published cases included 56% with growth restriction and/or short stature, 47% with developmental delays, 53% with cardiac defects, 49% with skeletal anomalies, and 38% with microcephaly. When parental testing was reported, 28 of 29 were found to be de novo.
PMID: 26991864
Bengoa-Alonso et al. (2016) compared clinical findings of patients from the literature with central region (B/C-D) deletions to those of patients with deletions from LCR22-C into the region between LCR22-D and -E (presumed LCR22-C to E recurrent deletions). A total of 9 individuals were reviewed, and the most common phenotypes included prematurity (89%), low birth weight (100%), microcephaly (78%), growth retardation (89%), congenital heart disease (89%), and developmental delay (67%), and hearing loss or ear abnormalities (44%).
Additional Case Reports:
PMID: 24938854
Manno et al. (2021) performed a retrospective analysis from 2,000 clinical chromosomal microarrays to identify individuals with 22q11.2 deletions. Three individuals from two families were identified with 22q11.2 D-E deletions (cases 13-15). These individuals presented with various findings including structural cardiac abnormalities, growth delay, speech delay, intellectual disability and other neurodevelopmental findings, and recurrent infections. Inheritance for case 13 was unknown. Cases 14 and 15 were a son and mother who were both clinically affected although the mother had milder clinical findings.
PMID: 29926511
Matsuo et al. (2019) reported the long-term natural history of an adult patient with a 22q11.2 D-E deletion. Their phenotype included short stature, microcephaly, cleft lip, microtia, aortic valve stenosis, and speech delay. Inheritance information was unavailable.
PMID: 29288792
Spineli-Silva et al. (2018) reported one individual with Oculo-auriculo-vertebral Spectrum (OAVS) with a 22q11.2 D-E deletion and reviewed the previous literature with a focus on OAVS. The authors noted 5 previously reported individuals with D-E (1), D-F (1), or D-G (3) deletions and features including craniofacial microsomia. The proband in this study also presented with congenital heart disease, short stature, microcephaly and speech and developmental delays. Inheritance information was unavailable.
PMID: 26247050
Lindgren et al. (2015) reported 3 individuals from two families with 22q11.2 D-E deletions including two siblings (patients 2 and 3). All three presented with pre- and/or postnatal growth restriction, speech and language delays, and two were delivered preterm due to preeclampsia. Inheritance information was unavailable for patient 1. The mother of patients 2 and 3 was tested and found to be negative for the deletion; the father with a history of mental illness was not tested.
PMID: 21671380
Tan et al. (2011) reported a patient (Patient 1) with a de novo 22q11.2 D-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.
Triplosensitivity (TS) Score Details
TS Score:
1
TS Evidence Strength:
Little Evidence for Triplosensitivity (Disclaimer)
TS Published Evidence:
-
PUBMED: 22140377
Wincent et al. (2011) reported 16 patients with distal 22q11.2 microduplications from 11,463 individuals referred to clinical genetic centers for genomic microarray and reviewed the clinical findings of patients from previously reported studies. Three of 16 patients had maternally inherited 22q11.2 D-E duplications. These individuals had variable phenotypes including mild to severe developmental delay, dysmorphic facial features and hypotonia. Second-site CNVs were identified in two of the three individuals and may contribute to the clinical findings in these patients. Of the 3 mothers carrying the duplication, one was clinically unaffected, one presented with learning and behavioral problems, and the phenotype was unknown for the third carrier mother.
-
PUBMED: 19193630
Coppinger et al. (2009) identified 18 patients with distal 22q11.2 microduplications from a cohort of 22,096 individuals referred for clinical genomic microarray testing. Two patients (subject 10 and subject 17) had 22q11.2 D-F duplications, one was de novo and the other of unknown origin. Additional phenotypic information was only available for subject 10, who presented with normal development at age 1 year 8 months, optic disc coloboma, mild dysmorphic features, contractures, and digital anomalies.
-
PUBMED: 18414210
Ou et al. (2008) reported 14 individuals from 8 families with duplications of the 22q11.2 region identified from approximately 7,000 individuals referred for clinical genomic microarray testing. One individual (patient 7) carried a 22q11.2 D-E duplication and presented developmental delay and mild facial dysmorphisms. Another individual had a 22q11.2 D-F duplication (patient 8) and had multiple congenital abnormalities and facial dysmorphisms. The duplication was paternally inherited in patient 7 (no learning difficulties were reported in the father) and of unknown origin in patient 8.
TS Evidence Comments:
Evidence in support of the pathogenicity of recurrent 22q11.2 (distal, LCR22-D to E/F) region duplication is limited at this time. Duplications of this region are rare in the literature, with 7 independent cases reported across 3 studies. Amongst affected carriers, clinical findings are mostly nonspecific, including developmental delay and other variable findings. Due to the limited number of reported cases with variable inheritance and lack of parental phenotype information, inheritance and penetrance are not well-understood. Case-control comparison studies have shown some evidence for enrichment of this duplication in clinical populations, though numbers are low. Due to limited number of reported cases, the triplosensitivity score is 1.
Additional relevant literature is summarized below:
Case-Control Studies:
PMID: 25217958
Coe et al. (2014) performed a large-scale case-control comparison study of the relative prevalence of CNVs in children with developmental delay/intellectual disability, multiple congenital anomalies, and other developmental phenotypes compared to controls. Duplications of the 22q11.2 D-E/F region were observed in 7/29,085 cases versus 0/19,584 controls (p= 0.027; LR Inf, 95% CI: 1.23-Inf), demonstrating enrichment of this duplication in the clinical population. See also Cooper et al. (2011) PMID 21841781, which uses an overlapping (older) dataset.
Report with atypical duplication, overlapping CNV evidence:
PMID: 26247050
Lindgren et al. (2015) reported 6 individuals with distal deletions or duplications in 22q11.2 identified using clinical genomic microarray testing. One patient presented an atypical 432 kb proximal duplication in the D-E region, encompassing MAPK1 gene (patient 4). The individual presented bilateral sensorineural hearing loss, myopia, strabismus, seizures and was in speech therapy. The inheritance of the duplication was unknown.
Genomic View
Select assembly:
(NC_000022.10)
()
