ClinGen Dosage Sensitivity Curation Page

1q21.1 recurrent (TAR syndrome) region (BP2-BP3, proximal) (includes RBM8A)

  • Curation Status: Complete
  • id: ISCA-37428
  • Date last evaluated: 2017-05-18
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 1
  • ClinGen Triplosensitivity Score: 1


Location Information

Select assembly: (NC_000001.10) ()
Evidence for haploinsufficiency phenotype
PubMed ID Description
22317977 Rosenfeld et al (2012) provided a clinical characterization of 22 individuals carrying deletions for this region who do not meet clinical criteria for TAR syndrome, an autosomal recessive disease caused by compound heterozygosity with mutation in the gene RBM8A. Features present in any one individual were variable, and features present in 50% or more of individuals included: failure to thrive/feeding problems and developmental delay/intellectual disabilities.
25217958 Coe et al. (2014) performed 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. 1q21 (BP2-BP3, RBM8A) proximal region deletions were observed in 25/29,085 cases versus 2/19,584 controls (p=1.63E-04), demonstrating enrichment of this deletion in the clinical population. See also Cooper et al. (2011) PMID 21841781 and Rosenfeld et al. (2013) PMID 23258348. NOTE: these comparisons are complicated by the apparent inclusion of patients with TAR syndrome in the clinical population used in these studies.

Haploinsufficiency phenotype comments:

The 1q proximal region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers deletions involving recurrent breakpoint (BP) regions BP2 and BP3, located in the proximal region of 1q21.1. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Evidence in support of a pathogenic role for deletion of this region is limited at this time. Although deletions of this region have been shown to be significantly enriched in the clinical population, prevalence estimates are complicated by apparent inclusion of TAR syndrome (compound heterozygosity for RBM8A gene mutation) patients in these estimates, and thus far there is only a single publication with phenotypic descriptions of proximal 1q21.1 deletion carriers, in whom the phenotype appears to be both variably expressive and incompletely penetrant. Therefore the current haploinsufficiency score is 1. Deletion of this region is a susceptibility factor for thrombocytopenia-absent radius (TAR) syndrome (OMIM 274000), an autosomal recessive disorder characterized by hypomegakaryocytic thrombocytopenia and bilateral radial aplasia in the presence of both thumbs. Most patients with TAR syndrome have a deletion of the proximal 1q21.1 region on one chromosome 1 homolog and a point mutation in the regulatory region for the gene RBM8A on the other chromosome 1 homolog (see Gene Reviews http://www.ncbi.nlm.nih.gov/books/NBK23758/ and Albers et al 2012; PMID: 22366785). Note also that cognitive development is usually normal in patients with TAR syndrome.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
22317977 Rosenfeld et al (2012) provided a clinical characterization of 20 individuals carrying duplications for this region. Features present in any one individual were variable, and features present in 50% or more of individuals included: developmental delay, intellectual disability, dysmorphic features, brain anomalies, failure to thrive/feeding problems, and behavioral problems.
25217958 Coe et al. (2014) performed 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, 1q21 (BP2-BP3, RBM8A) proximal region duplications were observed in 56/29,085 cases versus 11/19,584 controls (p=2.37E-05), demonstrating enrichment of this duplication in the clinical population. See also Cooper et al. (2011) PMID 21841781 and Rosenfeld et al. (2013) PMID 23258348.

Triplosensitivity phenotype comment:

The 1q proximal region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers duplications involving recurrent breakpoint (BP) regions BP2 and BP3, located in the proximal region of 1q21.1. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Evidence in support of the pathogenicity of duplication of this region is limited at this time. Although duplications of this region have been shown to be significantly enriched in the clinical population, thus far there is only a single publication with phenotypic descriptions of proximal 1q21.1 duplication carriers, in whom the phenotype appears to be both variably expressive and incompletely penetrant. Therefore the current triplosensitivity score is 1.