• 2
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
TBX1 (HGNC:11592) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
T-box transcription factor 1
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
VCF
Alias symbols
CATCH22
%HI
4.92(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.84(Read more about gnomAD pLI score)
LOEUF
0.43(Read more about gnomAD LOEUF score)
Cytoband
22q11.21
Genomic Coordinates
GRCh37/hg19: chr22:19744226-19771116 NCBI Ensembl UCSC
GRCh38/hg38: chr22:19756703-19783593 NCBI Ensembl UCSC
MANE Select Transcript
NM_001379200.1 ENST00000649276.2 (Read more about MANE Select)
Function
Transcription factor that plays a key role in cardiovascular development by promoting pharyngeal arch segmentation during embryonic development (By similarity). Also involved in craniofacial muscle development (By similarity). Together with NKX2-5, acts as a regulator of asymmetric cardiac morphogenesis by promoting expression of PITX2 (By similarity). Acts upstream of TBX1 for the formation of the thymus and parathyroid glands from the third pharyngeal pouch (By similarity). Required for hair f... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-31275
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Emerging Evidence for Haploinsufficiency (2)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
04/12/2022

Haploinsufficiency (HI) Score Details

HI Score:
2
HI Evidence Strength:
Emerging Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 14585638
    Yagi et al 2003 (PMID 14585638) 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.
  • PUBMED: 25860641
    Pan et al 2015 (PMID 25860641) identified a novel nonsense variant identified in proband from cohort of 230 individuals with congenital heart disease (CHD) with sequencing of TBX1 gene. Proband had double outlet right ventricle and ventricular septal defect. The variant co-segregated with CHD in autosomal dominant pattern in available relatives with complete penetrance. The variant was absent in 400 controls and was predicted to be LOF. Functional studies indicated the variant had no transcriptional activity compared to wild-type.
  • PUBMED: 29500247
    Basha et al 2018 (PMID 29500247) performed whole exome sequencing on 84 individuals with nonsyndromic cleft lip/palate from multiplex families. A nonsense variant found in a proband and mother, both with velopharyngeal insufficiency.
HI Evidence Comments:
There is extensive variability regarding terminology describing the phenotypes of 22q11.2 deletions in the literature, including, but not limited to; 22q11.2 deletion syndrome, velocardiofacial syndrome, DiGeorge syndrome. We have chosen the term velocardiofacial syndrome to encompass the different phenotypes ascribed to TBX1 loss of function in the literature. Based on these and other studies, there is emerging evidence that TBX1 mutations are responsible for several components of the velocardiofacial syndrome, particularly cardiac defects. Additional reports suggest phenotypes associated with loss of function of TBX1. Ogata et al 2014 (PMID 24637876) identified a frameshift variant that segregated with craniofacial features and hypocalcemia or craniofacial features alone. The variant was predicted to be a disease-causing mutation that escapes nonsense-mediated mRNA decay due to its position on the final exon, producing a truncated protein. Chen et al 2014 (PMID 23828768) identified an assumed de novo 0.85 kilobase deletion in a fetus with conotruncal heart defect. Aguayo-Gomez et al 2015 identified an assumed de novo deletion including exons 2-7 in a 19 year-old female with normal intellectual/social manifestation from a cohort of patients with tetralogy of Fallot. Paylor et al 2006 (PMID 16684884) 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. 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 (TS) Score Details

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

Genomic View

Select assembly: (NC_000022.10) (NC_000022.11)