• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
TBX22 (HGNC:11600) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
T-box transcription factor 22
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
CPX, CLPA
Alias symbols
No aliases found
%HI
43.82(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.98(Read more about gnomAD pLI score)
LOEUF
0.3(Read more about gnomAD LOEUF score)
Cytoband
Xq21.1
Genomic Coordinates
GRCh37/hg19: chrX:79270252-79287273 NCBI Ensembl UCSC
GRCh38/hg38: chrX:80014753-80031774 NCBI Ensembl UCSC
MANE Select Transcript
NM_001109878.2 ENST00000373296.8 (Read more about MANE Select)
Function
Probable transcriptional regulator involved in developmental processes. This is major determinant crucial to palatogenesis. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-18411
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
03/28/2023

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 11559848
    Braybrook et al. (2001) report several families with cleft palate and ankyloglossia (CPX) with variants in TBX22, including one nonsense (E56X;166G>T), one frameshift (664delC), two splice-site (IVS4+1G>A; IVS6+1G>C), and two missense variants. All six variants segregated with the disorder in the respective families, and none was 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.
  • PUBMED: 14729838
    Marcano ACB et al., (2004) described 5 variants in coding exons and 4 putative splicing variants in TBX22 gene in a cohort of 256 random CP patients with 18 being syndromic patients. Among them one frameshift mutation, 1056-106delGC was reported. In addition, a splicing mutation, IVS4+1G>A, in all 6 affected males in a four generation large family W; another missense, 790A>T (N264Y) in exon 5, all 4 affected males in a three generation family K.
  • PUBMED: 17868388
    Suphapeetiporn K et al. (2007) reported 4 unrelated Thai patients with apparently non-syndromic cleft palate and variants in TBX22, including one frameshift variant, 1252delG, 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. The other four potentially pathogenic missense mutations are 359G->A (R120Q), 452G->T (R151L), 1166C->A (P389Q).
  • PUBMED: 22784330
    Pauws E et al., (2013) reported three splice mutation (c.593-5T>A, c.767+5G>A and c.767+1G>A) in three affected individuals. The first one affecting acceptor side was tracked with the phenotype in a family; the latter two splice donor variants were identified in patients with classic CPX phenotypes. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome.
  • PUBMED: 25373698
    Fu X et al., (2015) reported a loss-of-function mutation, -73G>A, in the promoter of TBX22 gene in a six-generation family of the CPO (cleft palate only) with obvious phenotypes of both cleft palate and hyper-nasal speech. The mutation was detected in all five affected male members cosegregating with the affected phenotype and heterozygote occurred only in some unaffected females of the family, suggesting an X-linked transmission of the mutation in the family. Functional study using EMSA and ChiP assays, as well as cell con-transfection showed this mutation disrupts the binding site of ETS-1, thus markedly decreases the activity of the TBX22 promoter, which is likely to lead to the birth defect of the CPO without ankyloglossia.
  • PUBMED: 29932061
    Dai J et al., (2018) reported a novel essential splicing site mutation, IVS6-1G>C, in a family with cleft palate. The bioinformatic analysis results showed that this mutation would lead to abnormal transcription or translation, followed by a loss of function of TBX22.
HI Evidence 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. Additional information includes: PMID 12374769 Braybrook C et al., (2002) described a three nucleotide insertion, 581-582ins CAG (S195-196ins) in a Brazilian family and a missense mutation 641T>C (L214P) in exon 5 in family 1. PMID 17846996 Andreou AM et al., (2007) described 10 different naturally occurring missense mutations in the DNA-binding T-box domain that are phenotypically equivalent to loss-of-function alleles in patients with cleft palate. DNA binding and transcriptional repression, but not subcellular localization, are compromised by these missense CPX mutations. Missense changes are found exclusively within the T-box DNA-binding domain, suggesting defective binding to target promoter sequences as a common mechanism. Lack of DNA binding contributes significantly to TBX22 loss of function. The CPX (X linked cleft palate) phenotype caused by mutations in TBX22 most likely results from a loss of protein function. PMID 36294409 Biedziak B et al., (2022) reported a missense mutation, c.725C>T (p.Pro242Leu) in the T-box domain of a patient of non-syndromic tooth agenesis (ns-TA) from a cohort of 65 patients using NGS of 423 gene panel.
NOTE:

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 (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
NOTE:

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.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)