2q11.2 recurrent region (includes ARID5A, TMEM127)

  • 3
    Haplo
    Score
  • 1
    Triplo
    Score

Region Facts

Region Name
2q11.2 recurrent region (includes ARID5A, TMEM127)
Cytoband
2q11.2
Genomic Coordinates
GRCh37/hg19 chr2:96739012-97671429 NCBI Ensembl UCSC
GRCh38/hg38 chr2:96073264-97005692 NCBI Ensembl UCSC

Dosage Sensitivity Summary (Region)

Dosage ID:
ISCA-37495
Curation Status:
Complete
Issue Type:
Dosage Curation - Region
Description:
This review refers to the 2q11.2 recurrent region (includes ARID5A, TMEM127). Note that genes used as landmarks are not necessarily causative of the phenotype(s) associated with the region.  
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
Little Evidence for Triplosensitivity (1)
Related Links:
Last Evaluated:
02/21/2022

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Evidence:
  • PUBMED: 26227573
    Riley et al. (2015) reported clinical findings in four cases (five individuals total) with 2q11.2 deletions, including three unrelated individuals (Subjects 1-3) and two siblings (Subjects 4-5, Family 1) identified through routine clinical microarray testing. Clinical findings were summarized for these and a previously reported subject (Patient 2, Rudd et al., 2009; PMID 19443486). Phenotypes in common across these subjects included developmental delay/intellectual disability (including speech delay), ADHD, dysmorphic features, variable skeletal anomalies, and other variable findings. Inheritance was de novo in one case (Subject 2), paternally inherited in one case with the father noted to have “trouble in school” (Subject 1), maternally inherited in one case with no phenotypic information available (Subject 3), and for Family 1, no parental testing or phenotypic information was available. Inheritance for the deletion of Patient 2 reported by Rudd et al was unknown.
HI Evidence Comments:
The haploinsufficiency score for this region is based on evidence for a gene (TMEM127) encompassed by this region (see linked gene review). TMEM127 loss-of-function is associated with hereditary paraganglioma-pheochromocytoma syndrome. Therefore, the haploinsufficiency score is 3. In the context of neurodevelopmental phenotypes, the haploinsufficiency evidence is somewhat limited at this time. Deletions of this region are rare in the literature, with five independent cases reported across two studies. Amongst affected carriers, clinical findings are mostly nonspecific, including developmental delay/intellectual disability (including speech delay), ADHD, dysmorphic features, variable skeletal anomalies, 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 nominal enrichment of this deletion in clinical populations. 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 2q11.2 region were observed in 6/29,085 cases versus 0/19,584 controls (p=0.0455; LR: Inf, 95% CI: 1-Inf), demonstrating nominal enrichment of this deletion in the clinical population. See also Rosenfeld et al. (2013) PMID 23258348 and Cooper et al. (2011) PMID 21841781, which use overlapping (older) datasets. PMID: 27602560: Rees et al. (2016) performed a large-scale case-control comparison study of the relative prevalence of recurrent CNVs previously associated with neurodevelopmental phenotypes in a schizophrenia cohort compared to controls. Deletions of the 2q11.2 region were observed in 6/20,403 cases versus 1/26,628 controls (p=0.037, CMH OR=9.3 (1.03=447.76), demonstrating a nominal enrichment of this deletion in the clinical population. General Population Carrier Studies: PMID: 30767844 Kendall et al. (2019) analyzed the effect of the 2q11.2 deletion on cognitive performance and general measures of functioning of 31 deletion carrier adults recruited from the UK Biobank cohort (a large, genotyped group from the general population) compared to non-carrier controls from the same population. Significant differences were observed for 1 of 11 total measurements, including 0 of 7 cognitive measures and 1 of 4 measures of general functioning. Penetrance for any clinical phenotype associated with this deletion was estimated to be 13% using a previously reported clinical cohort compared to the UK Biobank control database.

Triplosensitivity (TS) Score Details

TS Score:
1
TS Evidence Strength:
Little Evidence for Triplosensitivity (Disclaimer)
TS Published Evidence:
  • PUBMED: 26227573
    Riley et al. (2015) reported clinical findings in two cases (three individuals total) with 2q11.2 duplications, including one individual (Subject 6) and two siblings (Subjects 7-8, Family 2) identified through routine clinical microarray testing. Clinical findings were summarized for these and a previously reported subject (Patient 1, Rudd et al., 2009; PMID 19443486). Phenotypes in common across these subjects included developmental delay/intellectual disability, dysmorphic features (frontal bossing, other variable features), short stature, variable skeletal anomalies, gastroesophageal reflux, and other variable findings. The duplication was maternally inherited in Family 2 with the mother noted to be unaffected (Subjects 7-8), and for Subject 6, it was not maternally inherited and the father was not available for testing but was noted to have learning difficulties and short stature. Inheritance for the duplication of Patient 1 reported by Rudd et al was de novo.
TS Evidence Comments:
Evidence in support of the pathogenicity of recurrent 2q11.2 duplication is limited at this time. Duplications of this region are rare in the literature, with three independent cases reported across two studies. Amongst affected carriers, clinical findings are mostly nonspecific, including developmental delay/intellectual disability, dysmorphic features, short stature, variable skeletal anomalies, gastroesophageal reflux, 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 not shown enrichment of this duplication in clinical populations. Therefore the triplosensitivity score is 1. Additional 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 2q11.2 region were observed in 4/29,085 cases versus 0/19,584 controls (p=0.128; LR: Inf, 95% CI: 0.559-Inf), with limited numbers and no evidence for enrichment of this duplication in the clinical population. See also Cooper et al. (2011) PMID 21841781, which uses an overlapping (older) dataset.

Genomic View

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