ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000022.10) (NC_000022.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
14585638 Yagi et al (2003) identified a heterozygous 1 base pair deletion (1223delC) in the TBX1 gene in a mother, son, and daughter with conotruncal anomaly face syndrome/velocardiofacial syndrome. The deletion caused a frameshift leading to a stop codon.
16684884 Paylor et al (2006) identified a heterozygous 23 base pair deletion (1320-1342del23) in the TBX1 gene in a mother and 2 sons with velocardiofacial syndrome. The deletion caused a frameshift and extension of the protein from 504 to 616 amino acids. Additional phenotypes in the family included major depression in the mother and Asperger syndrome in one of the sons. Using expression of a CAT-reporter protein as a read-out for transcriptional activity, they show that wild-type TBX1 activated the CAT reporter whereas the mutant constructs 1223delC (called 1250delC in this paper) and 1320-1342del23bp did not.

Haploinsufficiency phenotype comments:

Based on these and other studies, TBX1 mutations are responsible for several components of the del22q11.2 syndrome, particularly cardiac defects, but are not responsible for typical intellectual disability that is commonly seen in patients with del22q11.2 syndrome. Of note, Rauch et al (2010) identified a heterozygous 30 base pair duplication (1399-1428dup30) in exon 9c of the TBX1 gene in a patient with tetralogy of Fallot, facial asymmetry, scoliosis, absent pulmonary vein, isolated left pulmonary artery, and normal cognitive development. The duplication was not seen in the patient's normal mother or 185 controls. In cells transfected with either wild-type or mutant vector, the authors found normal mutant mRNA levels by RT-PCR. However, a luciferase transcriptional reporter assay showed severely reduced transcriptional activity of the mutant construct. In addition, the authors demonstrated aggregation of the protein in the cytoplasm by immunofluorescence studies (PMID:19948535). Another paper reports an 8 bp deletion in a patient that was inherited from a normal mother (PMID 11748311).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity