ClinGen Dosage Sensitivity Curation Page

2q21.1 recurrent region (includes ARHGEF4, GPR148)

  • Curation Status: Complete
  • id: ISCA-46288
  • Date last evaluated: 2019-09-30
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 1
  • ClinGen Triplosensitivity Score: 0


Location Information

Select assembly: (NC_000002.11) ()
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
22543972 Dharmadhikari et al. (2012) reported detailed clinical findings of five unrelated subjects (patients 1-5) with recurrent 2q21.1 deletions from a large cohort of patients (>17,000) referred for clinical microarray analysis. Clinical findings in common included DD/ID, ADHD, autism and epilepsy. Parental testing was performed for two patients (3 and 5), both of which were maternally inherited; the mother of patient 5 was reportedly unaffected and patient 3?s brother and mother were both affected carriers. Together these findings suggest reduced penetrance and/or variable expressivity. No deletions were observed in a control population of ~14,000 individuals or in the Database of Genomic Variants, suggesting enrichment for this CNV in the clinical population. The authors proposed that 2q21.1 recurrent deletions represent pathogenic CNVs and proposed ARHGEF4 and GPR148 as candidate genes in the region.
24591035 Gimelli et al. (2014) provided a detailed case report of a four-year old male with the recurrent 2q21.1 deletion who presented with ADHD, psychomotor delay, behavioral problems, language delay, mild dysmorphic features and tall stature. The deletion was inherited from the father who had childhood psychomotor delay and, as an adult, was treated for bipolar disorder.
25661985 Eriksson et al. (2015) identified a single patient with the recurrent 2q21.1 deletion from a cohort of 162 children with early diagnosed autism spectrum disorder studied by genomic microarray. Clinical findings included atypical autism, borderline IQ, cleft lip and palate and micrognathia. Inheritance for the deletion was maternal (no clinical information was provided).

Haploinsufficiency phenotype comments:

Deletion of the 2q21.1 region (~450 kb, 5 genes) has been reported in at least seven unrelated patients in the literature. Reported clinical findings are variable, but typically include neurobehavioral phenotypes and developmental delays. In the four cases where parental testing has been performed, these deletions were found to be inherited; at least one deletion was identified in an unaffected parent. Due to a limited number of observed deletions and lack of enrichment in the clinical population, the penetrance for 2q21.1 deletions is currently not well-understood. There is currently limited evidence to support haploinsufficiency for this region, therefore the haploinsufficiency score is 1. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Case-control studies PMID: 25217958 Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, deletions of the recurrent 2q21.1 region were observed in 6/29,085 cases (4 typical deletions + 2 deletions with breakpoints inside the event >50% unique space coverage) versus 2/19,584 controls. Statistical values (counting 4 typical cases): p= 0.5394 LR+ = 1.35 (0.237 to 9.23), Penetrance = 6.77% (1.26 to 33.2%); (using all 6 cases): p= 0.3104, LR+ = 2.02 (0.425 to 12.2), Penetrance = 9.84% (2.24 to 39.7%). These findings lack evidence for enrichment in the clinical population.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
22543972 Dharmadhikari et al (2012) reported five unrelated subjects (patients 6-10) with recurrent 2q21.1 duplications from a large cohort of patients (>17,000) referred for clinical microarray analysis. Detailed clinical findings were not obtained. Clinical indications provided for the duplication subjects were variable; several presented with intellectual disability, developmental delay, and autism. One subject did not demonstrate a neurodevelopmental phenotype and only had cardiac defects. Parental testing was performed for two patients (7 and 9), both of which were paternally inherited. The father of patient 7 was reportedly unaffected. Patient 9?s carrier father was affected, however the proband?s family history included six of nine siblings affected with autism, Asperger syndrome or epilepsy, and only one of these siblings was reported to carry 2q21 duplication (all siblings were tested). A single control subject was found with the duplication in a population of ~8800 controls. The authors concluded, ?the clinical consequences of the 2q21.1 duplication are unknown at this time.?

Triplosensitivity phenotype comment:

Although duplications involving the 2q21.1 region (~450 kb, 5 genes) in the clinical population have been reported in at least one study, detailed clinical information was limited for these patients and clinical findings were highly variable, with at least one familial case showing some evidence of non-segregation of affected status with the 2q21.1 duplication. Due to a limited number of observed duplications and lack of enrichment in the clinical population, the penetrance for 2q21.1 duplications is currently not well-understood. There is currently insufficient evidence to support triplosensitivity for this region, therefore the triplosensitivity score is 0. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Case-control studies PMID: 25217958 Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, duplications of the recurrent 2q21.1 region were observed in 1/29,085 cases versus 5/19,584 controls. Statistical values: p= 0.9958, LR+ = 0.135 (0.0088 to 1) Penetrance = 0.721% (0.0475 to 5.12%). These findings lack evidence for enrichment in the clinical population (personal communication; not listed in the supplemental data).