ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000017.10) (NC_000017.11)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
28372585 Qian et al (2017) reported a frameshift mutation in a patient with Tetralogy of Fallot (TOF) and atrioventricular septal defect within cohort of 106 patients with TOF tested for genetic causes using a 29 gene sequencing panel.

Haploinsufficiency phenotype comments:

Thus far, a single patient with a frameshift (presumed LOF) variant of TBX2 has been reported. Therefore the haploinsufficiency score is 1. Additional relevant literature is summarized below: PMID 29726930: Liu et al. 2018 reported four patients with craniofacial dysmorphisms, cardiac anomalies, skeletal anomalies, immune deficiency, endocrine anomalies and developmental delay with missense mutations in TBX2. Patients included one family with two siblings and a more mildly affected mother as well as one patient with a de novo mutation. Functional studies show reduced activity of transcriptional repressor, reduced protein levels and suggest partial loss of function alleles. PMID 23727221: Pang et al (2013) identified four novel heterozygous DSVs (DNA sequence variants) within the TBX2 gene promoter in VSD (ventricular septal defects) patients, which significantly decreased transcriptional activities of the TBX2 gene promoter. These results suggested that these DNA sequence variants may change TBX2 levels, contributing to VSD etiology.

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

Triplosensitivity phenotype comment:

Focal duplication of TBX2 has not been reported in association with clinical phenotypes. Therefore the triplosensitivity score is 0. Additional relevant literature is summarized below: PMID 20635360: Radio et al (2010) reported a four year old male patient with mild intellectual disability, minor dysmorphic features and skeletal anomalies, complex heart defect, laryngomalacia, cerebellar, pons and medulla hypoplasia, and Duane anomaly. Patient was found to have a de novo 131 kb duplication including all of TBX2 as well as C17orf82, and a portion of BCAS3. Authors propose heart malformation and mild digital anomalies in the patient could be related to gene overexpression.