ClinGen Dosage Sensitivity Curation Page

TBX22

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11559848 Braybrook et al. (2001) report several families with cleft palate and ankyloglossia (CPX) with variants in TBX22, including one nonsense, one frameshift, two splice-site, and two missense variants. All six variants segregated with the disorder in the respective families, and none were present in 200 control chromosomes. The authors note that they "attempted to amplify cDNA from across the splice-site mutation in a cell line from an Icelandic male with cleft palate and ankyloglossia, [and were unable to] detect any PCR product, even with primer pairs from other portions of the transcript..." They hypothesize that the particular splice site variant may result in nonsense-mediated decay.
17868388 Suphapeetiporn et al. (2007) report 4 unrelated Thai patients with apparently non-syndromic cleft palate and variants in TBX22, including one frameshift variant predicted to result in premature termination. This variant was found in a female with non-syndromic cleft palate and her father with bifid uvula. A paternal uncle was reported to have isolated cleft soft palate, but no testing was done on this individual. The variant was not found in 112 ethnically-matched unaffected control chromosomes.

Haploinsufficiency phenotype comments:

A number of the variants in TBX22 reported in association with cleft palate with ankyloglossia have been missense. Andreou et al. (2007) (17846996) studied ten different missense variants in TBX22 (previously identified in affected patients). The authors reported that "DNA-binding assays indicate that missense mutations at or near predicted contact points with the DNA backbone compromise stable DNA-protein interactions." They also show that "TBX22 functions as a transcriptional repressor and that TBX22 missense mutations result in impaired repression activity." They go on to suggest that all TBX22 variants resulting in demonstrable phenotypes in patients have a similar functional result: loss of the ability of the protein to bind DNA. Phenotypic variability, even among families, has been observed. Females are most often unaffected; those females who are affected more frequently have anklyoglossia, not necessarily cleft palate. Of note, a single report (PMID:22784330) has described a family with deafness and coloboma (Abruzzo-Erikson syndrome) in addition to cleft palate and ankyloglossia, and a variant in TBX22. More information is necessary to determine the validity of this association.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

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

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.