ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000006.11) (NC_000006.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
27452334 Ackerman et al (2016) identified a de novo nonsense mutation (p.Y497X) in TAB2 in a boy with mild pulmonary valve stenosis and mild aortic root dilatation, and an atrial septal defect, ventricular septal defect, and patent ductus arteriosus. He also had hypotonia, myopia, soft pale skin, joint hypermobility, and mild facial dysmorphism.
28464518 Cheng et al (2017) described 13 individuals with microdeletions of chromosome 6q25.1 that involve TAB2 gene. One of these patients has the smallest deletion yet reported (120kb), affecting only TAB2 but unknown inheritance. Another patient has a 260kb de novo deletion compraising TAB2. These patients were compared to 27 other previously reported in the literature and DECIPHER with similar microdeletions, for a total study group of 40 patients. The authors showed that individuals with TAB2 deletions are predisposed to developing a primary cardiomyopathy with reduced systolic function, even in the absence of CHD. Other non-cardiac phenotypic findings were identified in patients with larger deletions compraising other genes: Dysmorphic facial features, intrauterine growth restriction and/or postnatal proportionate short stature, hypotonia, developmental delay and connective tissue abnormalities.
31959127 Chen et al (2020) described a three-generation family that included five CHD patients with heart valvular defect (mitral or tricuspid valves prolapse or regurgitation, and aortic valve stenosis or regurgitation). A nonsense variant in TAB2 (c.C446G, p.S149X), which results in the elimination of the critical TAK1-binding domain, was identified in all affected patients but not in the eight unaffected family members.

Haploinsufficiency phenotype comments:

There are several other publications reporting cardiac abnormalities in individuals with larger deletions involving TAB2 (in addition to other genes) (see below). Though TAB2 has been postulated to be the causative gene for this phenotype, the effects of losing these other genes cannot be ruled out, and additional cases involving loss of TAB2 alone are needed to further support this claim: Thienpont et al (2010, PMID: 20493459) describe aCGH screening studies for individuals who had previously been reported with deletions of 6q. Of the individuals with heart defects, all of them were deleted for TAB2 and 5 other genes. Those individuals for whom no heart defect had been reported previously, the deletions prompted a cardiac examination, and individuals deleted for those 5 genes were also found to have valvular heart defects. Those with larger deletions also often had other clinical features. Additionally, a family with a t(2;6) that disrupts TAB2 was identified with heart defects in all translocation carriers. Functional TAB2 knock-down studies in zebrafish demonstrated reduced expression of TAB2 resulted in impaired cardiac development. Salpietro et al (2015, PMID: 25940952) describe a girl with a de novo 630 kb deletion of 8 genes, including TAB2. She presented with heart defects, skin elasticity, hyperextensible joints, growth restriction, developmental delay, and cerebral ventricular asymmetry. Based on the Theinpont article, the authors propose that loss of TAB2 is responsible for her heart defect. Weiss et al (2015, PMID: 26139517) describe a 3-generation family with a 281 kb deletion of TAB2 and 3 other genes who all have heart defects, including Tetralogy of Fallot, prolapsed valves, ASD, VSD. The carrier mother also had similar heart defects but never required surgical repair. The maternal grandmother was also a carrier with heart defects. The grandmother's first pregnancy was a demise of a male that was noted to have heart defects, although no genetic testing was performed. A healthy maternal aunt did not have the deletion.

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