22q11.2 recurrent region (distal type II, E-F) |
- 1
Haplo
Score - 1
Triplo
Score
Dosage Sensitivity Summary (Region)
Dosage ID:
ISCA-37488
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-E and -F, often referred to in the literature as the distal type II region.
Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region.
NOTE: Curation of overlapping, larger CNVs involving the LCR22-D to E/F (distal type I), LCR22-D to G/H and LCR22-E/F to -H (distal type III) regions are linked below.
Haploinsufficiency:
Little Evidence for Haploinsufficiency
(1)
Triplosensitivity:
Little Evidence for Triplosensitivity
(1)
Related Links:
Last Evaluated:
01/19/2023
Haploinsufficiency (HI) Score Details
HI Score:
1
HI Evidence Strength:
Little Evidence for Haploinsufficiency
(Disclaimer)
HI Evidence:
-
PUBMED:
23765049
Mikhail et al. (2014) reported 4 patients with 22q11.2 E-F deletions. Clinical findings were variable, but included developmental delay, intellectual disability, and language delays. Craniofacial dysmorphism was noted in two cases. Inheritance was de novo in 2 cases and unknown in the other 2 cases.
-
PUBMED:
26278718
Burnside (2015) provided a combined clinical summary of patients with 22q region deletions identified by both clinical microarray testing and comprehensive literature review. For 22q11.2 E-F region deletions, a total of 8 postnatal patients from the literature and 3 novel prenatal cases were summarized. Clinical features amongst the postnatal cases were highly variable with the most common features being developmental delay, intellectual disability, language delay, and dysmorphic features. Of the 3 novel prenatal cases, abnormal ultrasound findings were reported in 2 cases (cardiac defect and increased nuchal translucency) and 1 case had parental testing (inherited). Parental phenotypes were not provided.
-
PUBMED:
31837127
Winberg et al. (2020) screened 25 patients with anorectal malformations (ARM), esophageal atresia, or hydronephrosis using chromosomal microarrays. One patient was found to carry a 22q11.2 E-F deletion that was inherited from an unaffected father. The patient had ARM, vertebral defects, and a congenital heart defect.
-
PUBMED:
21278390
Nik-Zainal et al. (2011) identified a patient with the 22q11.2 E-F deletion from a cohort of patients with syndromic and non-syndromic Mullerian aplasia. Clinical findings in this patient included Mullerian aplasia, craniofacial dysmorphism, congenital heart defects, fused pelvic kidney, skeletal/digital anomalies, and multiple nevi. The patient's psychomotor development was normal at age 16 years. Inheritance was unknown.
-
PUBMED:
17351135
Shaikh et al. (2007) reported a patient with the 22q11.2 E-F deletion. Clinical findings included mild craniofacial dysmorphism, short stature, pectus excavatum, developmental delay, and speech apraxia. Inheritance was unknown.
-
PUBMED:
21948486
Rauch et al. (2005) reported a patient with a paternally inherited 22q11.2 E-F deletion. Clinical findings included mild craniofacial dysmorphism and congenital heart defects. The patient's psychomotor development was normal at 8 months of age. The father showed mild craniofacial dysmorphism and normal psychomotor development.
HI Evidence Comments:
Deletion of the 22q11.2 distal E-F region has been reported in a limited number of cases in the literature with variable and sometimes inconsistent clinical findings. Amongst reported affected individuals, clinical findings in common include developmental delay (including language delay), intellectual disability, learning disability, mild facial dysmorphism, and congenital heart defects. Inheritance and parental phenotype status information are limited; therefore, penetrance is not well-understood. Current case-control data provide some evidence for enrichment in the clinical population. Therefore, the haploinsufficiency score is 1.
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 E-F region were observed in 12/29,085 cases versus 2/19,584 controls (p= 0.038; LR: 4.04, 95% CI: 1.01-20.7), providing evidence for enrichment of this deletion in the clinical population. See also Cooper et al. (2011) PMID 21841781, which uses an overlapping (older) dataset.
Additional relevant literature is summarized below:
PMID: 21849782
Yu et al. (2011) reported a patient with a de novo 22q11.2 E-F deletion. However, this patient also carried a 5.75 Mb terminal deletion of 1p36.31, which likely contributed to the phenotype. Clinical findings included dysmorphic features (not otherwise specified), failure to thrive, and seizures.
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 2 patients with duplication of the 22q11.2 E-F region. One patient presented with mild developmental delay, dysmorphic features, and speech disability. The other patient presented with severe developmental delay, autism, epilepsy, and absence of septum pellucidum. One patient inherited the duplication from an unaffected mother while inheritance information was unavailable for the other patient.
TS Evidence Comments:
Evidence in support of the pathogenicity for the 22q11.2 distal E-F duplication is limited at this time. Duplications of this region are rare in the literature. Amongst affected carriers, clinical findings are mostly nonspecific and variable with limited parental inheritance information. Current case-control information provides limited evidence for enrichment in the clinical population. Therefore, the triplosensitivity score is 1.
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 E-F region were observed in 7/29,085 cases versus 3/19,584 controls (p= 0.37; LR: 1.57, 95% CI: 0.415-6.7), providing limited evidence for enrichment in the clinical population, based only on likelihood ratio. See also Cooper et al. (2011) PMID 21841781, which uses an overlapping (older) dataset.
Additional relevant literature is summarized below:
PMID: 26640714
Sedghi et al. (2015) identified a patient with a 22q11.2 distal E-F duplication. This study used MLPA targeting chromosome 22q11.2 to study a cohort of 378 patients with cleft lip and/or palate. Duplication of probes from GNAZ to RAB36 was identified, which is suggestive of duplication of 22q11.2 E-F. This patient presented with cleft palate, craniofacial dysmorphisms, learning disability, and behavioral abnormalities. The duplication was inherited from an unaffected mother.
PMID: 34621295
Servetti et al. (2021) reported a patient with a 22q11.2 distal E-F duplication from a cohort of 12 patients with complex neurodevelopmental disorder phenotypes and multiple CNVs. The patient presented with atypical behaviors, attention disorder, and hyperactivity. Their 22q11.2 E-F duplication was inherited from an apparently unaffected mother. This patient also had 2 additional CNVs, both classified as VUS: a maternally inherited duplication on chromosome 12 (409 kb, including WSCD2) and a de novo duplication on chromosome 14 (760 kb, including ABHD4).