ClinGen Dosage Sensitivity Curation Page

2q11.2 recurrent region (includes ARID5A, LMAN2L)

  • Curation Status: Complete
  • id: ISCA-37495
  • Date last evaluated: 2020-02-28
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 1
  • ClinGen Triplosensitivity Score: 1


Location Information

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  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
26227573 Riley et al. (2015) report four new cases (five individuals total), three unrelated individuals (Subjects 1-3) and two siblings (Subjects 4-5, Family 1), with recurrent 2q11.2 deletions. Deletion of Subject 1 was paternally inherited with the father noted to have ?trouble in school?. The deletion of Subject 2 was de novo. The deletion of Subject 3 was maternally inherited (no phenotypic information available). Subjects 4 and 5 are similarly affected siblings (no parental phenotype information). Clinical findings in common across patients include: speech delay, ADHD, and dysmorphic features.
19443486 Rudd et al. (2009) analyzed array CGH data of 2419 individuals in an effort to identify new syndrome-associated segmental duplication-mediated chromosome rearrangements. This study described one individual (Patient 2, Table 1) with deletion of the recurrent 2q11.2 region. This individual had clinical features that included learning disabilities, ADHD, scoliosis, cafe au lait spots, and aortic coarcation requiring surgical repair. The inheritance was unknown. The deletion was not identified in an unpublished control population, which included 347 unaffected parents of schizophrenia probands and 529 Ashkenazi Jewish patients with Crohn?s disease, dystonia or Parkinson?s disease (n=876).

Haploinsufficiency phenotype comments:

Evidence in support of the pathogenicity of recurrent 2q11.2 deletion* is limited at this time. Five independent 2q11.2 deletion cases have been reported across two studies. Amongst affected carriers, clinical findings in common are nonspecific. The associated phenotypes include speech delay, ADHD, dysmorphic features and additional variable findings. Inheritance information is not well-understood (known in four cases): one case was de novo, three cases involve inheritance, but parental phenotypes are unknown/not well-characterized. In addition, nominal statistical significance has been observed from case-control comparison (reviewed below); observed deletions in both populations are relatively rare (wide CIs for OR/LR, lower bound <2). Therefore the haploinsufficiency score is 1. *The proximal 2q region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to deletions involving recurrent breakpoints within the 2q11.2 region (ARID5A, LMAN2L included). Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Additional literature is summarized below: 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 2q11.2 (ARID5A, LMAN2L) region were observed in 6/29,085 cases versus 0/19,584 controls (p=0.455; LR: Inf, CI: (1 to Inf)), demonstrating a nominal level of significance in support of enrichment this deletion in the clinical population. See also Cooper et al. (2011), PMID 21841781.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
26227573 Riley et al. (2015) report two new cases (three individuals total), one individual (Subject 6) and two siblings (Subjects 7-8, Family 2), with recurrent 2q11.2 duplications. Subjects 7 and 8 are similarly affected siblings and the duplication was inherited from an unaffected mother. The duplication of Subject 6 was not maternally inherited and the father was not available for testing but was noted to have learning difficulties and short stature. Clinical findings in common across patients include: developmental delay, dysmorphic features (frontal bossing, other minor features), gastroesophageal reflux, and short stature.
19443486 Rudd et al. (2009) analyzed array CGH data of 2419 individuals in an effort to identify new syndrome associated segmental duplication-mediated chromosome rearrangements. This study described one individual (patient 1, table 1) with duplication of the recurrent 2q11.2 region. This individual had clinical features that included developmental delay, short stature, midface hypoplasia, macrocephaly, significant brachydactyly, and hypotonia. The duplication was confirmed to be de novo. The duplication was not identified in 876 control individuals, which included 347 unaffected parents of schizophrenia probands and 529 Ashkenazi Jewish patients with Crohn?s disease, dystonia or Parkinson?s disease (n=876).

Triplosensitivity phenotype comment:

Evidence in support of the pathogenicity of recurrent 2q11.2 duplication* is limited at this time. Three independent 2q11.2 duplication cases have been reported across two studies. Amongst affected carriers, clinical findings in common are relatively nonspecific, but somewhat consistent, including DD, dysmorphic features, short stature, and gastrointestinal reflex. Inheritance information is not well-understood (known in two cases): one case was de novo, the other was inherited from an unaffected parent (mother). In addition, statistical significance has not been observed from case-control comparison (reviewed below); observed duplications in both populations are relatively rare (wide CIs for OR/LR, lower bound <1).Therefore the triplosensitivity score is 1. *The proximal 2q region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to duplications involving recurrent breakpoints within the 2q11.2 region (ARID5A, LMAN2L included). Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Additional literature is summarized below: 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 2q11.2 (SNRNP200, LMAN2L, TMEM127) region were observed in 4/29,085 cases versus 0/19,584 controls (p= 0.128; LR=INF (0.559-INF)), demonstrating a lack of enrichment of this duplication in the clinical population. See also Cooper et al. (2011), PMID 21841781.