TBX1

Summary

TBX1 (T-box transcription factor 1, HGNC:11592) is a protein-coding gene on chromosome 22q11.21, encoding T-box transcription factor TBX1 (O43435). Transcription factor that plays a key role in cardiovascular development by promoting pharyngeal arch segmentation during embryonic development.

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene product shares 98% amino acid sequence identity with the mouse ortholog. DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS), a common congenital disorder characterized by neural-crest-related developmental defects, has been associated with deletions of chromosome 22q11.2, where this gene has been mapped. Studies using mouse models of DiGeorge syndrome suggest a major role for this gene in the molecular etiology of DGS/VCFS. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 6899 — RefSeq curated summary.

At a glance

• Gene–disease (curated): conotruncal heart malformations (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 1,196 total — 46 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 218
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• Transcription factor: yes — 17 downstream targets (CollecTRI)
• MANE Select transcript: NM_001379200

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11592
Approved symbol	TBX1
Name	T-box transcription factor 1
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Aliases	CATCH22
Ensembl gene	ENSG00000184058
Ensembl biotype	protein_coding
OMIM	602054
Entrez	6899

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 2 retained_intron

ENST00000329705, ENST00000332710, ENST00000359500, ENST00000475303, ENST00000484336, ENST00000649276, ENST00000680333, ENST00000700274

RefSeq mRNA: 4 — MANE Select: NM_001379200 NM_001379200, NM_005992, NM_080646, NM_080647

CCDS: CCDS13765, CCDS13766, CCDS13767, CCDS93119

Canonical transcript exons

ENST00000649276 — 7 exons

Exon	Start	End
ENSE00001302335	19766389	19767334
ENSE00001313651	19764958	19765113
ENSE00001317346	19763241	19763342
ENSE00001330873	19765902	19766002
ENSE00001778543	19764155	19764326
ENSE00003461701	19765758	19765825
ENSE00003837211	19760778	19761280

Expression profiles

Bgee: expression breadth ubiquitous, 220 present calls, max score 93.59.

FANTOM5 (CAGE): breadth broad, TPM avg 6.7576 / max 204.4566, expressed in 600 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191068	5.5738	564
191062	0.8979	140
191069	0.1019	52
209387	0.0788	33
209386	0.0589	32
191063	0.0463	16

Top tissues by expression

268 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	93.59	gold quality
gastrocnemius	UBERON:0001388	91.55	gold quality
muscle of leg	UBERON:0001383	89.88	gold quality
biceps brachii	UBERON:0001507	89.61	gold quality
tendon of biceps brachii	UBERON:0008188	89.20	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	88.69	gold quality
muscle organ	UBERON:0001630	87.80	gold quality
endometrium epithelium	UBERON:0004811	87.69	silver quality
sperm	CL:0000019	85.42	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.38	gold quality
male germ cell	CL:0000015	84.01	gold quality
vastus lateralis	UBERON:0001379	84.01	gold quality
right lobe of thyroid gland	UBERON:0001119	83.72	gold quality
quadriceps femoris	UBERON:0001377	83.70	silver quality
paraflocculus	UBERON:0005351	83.64	silver quality
right testis	UBERON:0004534	83.33	gold quality
left lobe of thyroid gland	UBERON:0001120	82.82	gold quality
left testis	UBERON:0004533	82.74	gold quality
skin of abdomen	UBERON:0001416	82.53	gold quality
thyroid gland	UBERON:0002046	81.72	gold quality
tibialis anterior	UBERON:0001385	81.55	silver quality
middle frontal gyrus	UBERON:0002702	81.38	silver quality
skeletal muscle tissue	UBERON:0001134	81.18	gold quality
ectocervix	UBERON:0012249	80.89	gold quality
testis	UBERON:0000473	80.64	gold quality
left uterine tube	UBERON:0001303	79.91	gold quality
skin of leg	UBERON:0001511	79.90	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	79.82	gold quality
nasal cavity epithelium	UBERON:0005384	79.06	silver quality
nasal cavity mucosa	UBERON:0001826	79.04	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-11268	yes	643.46
E-ANND-3	yes	3.27
E-MTAB-6142	no	1.71

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

17 targets.

Target	Regulation
AMELX	Activation
ARRB2
BMP4
CDKN1A	Unknown
EYA1
FGF10	Unknown
FGF8	Unknown
FLT4	Activation
HPGDS
PITX2	Repression
PTGDR
SLU7
SOX9	Activation
TBX1
TBXT
TLX1	Unknown
UGT1A1

JASPAR motifs

Motif	Name	Family
MA0805.1	TBX1	TBX1-related factors

JASPAR matrix evidence (PMIDs): PMID:12093383

Upstream regulators (CollecTRI, top): NR4A3, PITX2, TBX1

miRNA regulators (miRDB)

28 targeting TBX1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-4700-5P	98.63	67.43	1915
HSA-MIR-637	97.91	64.05	1517
HSA-MIR-8089	97.74	66.21	1698
HSA-MIR-4667-5P	97.61	66.67	1683
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-4485-5P	95.91	59.69	198
HSA-MIR-3651	95.62	64.67	287
HSA-MIR-10396B-5P	94.99	63.57	358
HSA-MIR-1908-5P	94.99	63.41	352
HSA-MIR-663A	94.99	63.54	378
HSA-MIR-4508	90.37	59.62	240
HSA-MIR-6889-5P	90.26	64.13	291
HSA-MIR-6777-5P	88.76	62.64	222
HSA-MIR-6499-5P	87.01	61.21	38
HSA-MIR-4767	86.06	61.02	43
HSA-MIR-1469	65.89	55.19	6

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects (PMID:11748311)
• identified a single cis-element upstream of Tbx1 that recognized winged helix/forkhead box (Fox)-containing transcription factors (PMID:12533514)
• Genetic dissection of the DiGeorge syndrome phenotype. (PMID:12858556)
• Mutations in TBX1 are not likely to be involved in the cardiac phenotype observed in del22q11 patients. (PMID:15337468)
• a novel nuclear localization signal in Tbx1 is deleted in DiGeorge syndrome patients harboring the 1223delC mutation (PMID:15703190)
• role for Tbx1 in mediating epithelial-mesenchymal signalling in regions of the developing face (PMID:16586352)
• Data show that deficits in prepulse inhibition, a behavioral abnormality and schizophrenia endophenotype, in Df1/+ mice are caused by haploinsufficiency of two genes, Tbx1 and Gnb1l. (PMID:16684884)
• TBX1 missense mutations cause gain of function resulting in Shprintzen syndrome (PMID:17273972)
• screen for TBX1 gene mutations identified 2 mutations in patients with some features compatible with 22q11.2-deletion syndrome but with no deletions. (PMID:17377518)
• T-box transcription factor and a molecule implicated in mesodermal developmecan may be a potential target for human T-cell-mediated cancer immunotherapy. (PMID:17438107)
• TBX1 variation does not make a strong contribution to the genetic etiology of nonsyndromic forms of psychiatric disorders commonly seen in patients with 22q11DS. (PMID:17622328)
• Our data suggest that the genetic polymorphisms within TBX1 do not confer an increased susceptibility to schizophrenia in the Chinese population. (PMID:17850965)
• T-bet expression does not inhibit interferon-alpha-dependent interleukin-2 secretion in human T(central memory) cells. (PMID:19050236)
• Fluorescent in situ hybridisation analysis on FGFR4, ETS2 and brachyury failed to show either amplification or translocation for ERG and ETS2 loci (PMID:19407855)
• Atypical deletion of 22q11.2 detection using the FISH TBX1 probe and molecular characterization with high-density SNP arrays is reported. (PMID:19467348)
• Brachyury is overexpressed in various human tumor tissues and tumor cell lines compared with normal tissues. (PMID:20071775)
• Studies indicate that mutations in the TBX1 gene have been found in patients with phenotypes reminiscent of 22q11.2 syndromes. (PMID:20497193)
• This is the first comprehensive investigation of common and rare TBX1 genetic variants in non-syndromic tetralogy of Fallot cases and it has identified a rare novel functional genetic variant that is a likely susceptibility factor to tetralogy of Fallot. (PMID:20937753)
• common DNA variations in TBX1 do not explain variable cardiovascular expression in 22q11DS patients, implicating existence of modifiers in other genes on 22q11.2 or elsewhere in the genome (TBX1 ) (PMID:21796729)
• TBX1 T-box domain binds DNA as two distinct monomers. (PMID:22095455)
• Brachyury and related Tbx proteins interact with the Mixl1 homeodomain protein and negatively regulate Mixl1 transcriptional activity (PMID:22164283)
• TBX1 genetic variants may be associated with conotruncal heart defects. (PMID:22185286)
• The sequence variants within TBX1 gene promoter may contribute to the ventricular septal defect etiology by altering the expression levels of TBX1 gene. (PMID:22801995)
• TBX1 can alter TGF-beta/BMP, an important signaling pathway, through interacting with HOXD10. Above findings may shed light on the mechanism of TBX1 mutations leading to renal malformations found in patients carrying a 22q11 deletion. (PMID:22842189)
• We describe eight patients with variable phenotype features harboring atypical distal deletions of chromosome 22q11.2 not encompassing the TBX1 gene. (PMID:22893440)
• shRNA silencing of the T-box transcription factor Brachyury resulted in downregulation of the EMT and stem cell markers in adenoid cystic carcinoma cell lines. Brachyury expression in clinical samples of AdCC was extremely high and closely related to EMT. (PMID:22931165)
• common DNA variants in TBX1 may be nominally causative for CP in patients with 22q11DS. This raises the possibility that genes elsewhere on the remaining allele of 22q11.2 or in the genome could be relevant. (PMID:23034814)
• Findings indicate an association between TBX1 variations and fetal CTD. The results also demonstrate the power of array CGH to further scrutinize the critical gene(s) of del22q11.2 syndrome responsible for heart defects. (PMID:23828768)
• Results show that TBX1 regulates brain angiogenesis through the DLL4/Notch1-VEGFR3 regulatory axis. (PMID:23945394)
• DNA sequence variants within the TBX1 gene promoter may change TBX1 level, contributing to indirect inguinal hernia development as a rare risk factor (PMID:24295890)
• TBX1 isoform C is the biologically essential variant and that TBX1 mutations are associated with a wide phenotypic spectrum, including most of 22q11.2DS phenotypes. (PMID:24637876)
• Observations suggest that TBX1 loss-of-function mutation may be involved in the pathogenesis of isolated conotrucal heart defects (CTDs)in patients without 22q11.2 deletion. (PMID:24998776)
• SNPs in three genes CYP26B1 rs2241057, CISD1 rs2251039, rs2590370, and TBX1 rs4819522 were involved in six potential pathways to influence serum prostate-specific antigen levels. (PMID:25168891)
• TBX1 loss-of-function mutation with enhanced susceptibility to double outlet right ventricle (DORV) and ventricular septal defect (VSD)in humans, which provides novel insight into the molecular mechanism underlying Congenital heart disease (CHD). (PMID:25860641)
• The results clearly suggest a possible etiologic association between the TBX1 deletion and Tetralogy of Fallot. (PMID:26036351)
• A genome wide are study to identify acute kidney injury risk in critically ill patients identified a locus on chromosome 22 found 140kb upstream of TBX1, and may affect pathways that contribute to AKI pathophysiology. (PMID:27576016)
• a mutation, c.303-305delGAA, located in the third exon of TBX1 that does not disrupt TBX1 mRNA expression or DNA binding activity, but results in decreased TBX1 protein levels and transcriptional activity. (PMID:28272434)
• Studied expression, function, and regulation of T-box transcription factor (TBX1), in human parathyroid adult normal and tumor tissues. (PMID:28920943)
• We identified rare damaging variants in four genes known to be mutated in syndromic lip and/or cleft palate (syCL/P) : TP63 (one family), TBX1 (one family), LRP6 (one family) and GRHL3 (two families), and clinical reassessment confirmed the isolated nature of their lip and/or cleft palate (CL/P). (PMID:29500247)
• PCR and western blotting demonstrated that TBX1 expression may be associated with congenital heart disease. (PMID:29568912)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	tbx1	ENSDARG00000031891
mus_musculus	Tbx1	ENSMUSG00000009097
rattus_norvegicus	Tbx1	ENSRNOG00000001892
drosophila_melanogaster	H15	FBGN0016660
drosophila_melanogaster	mid	FBGN0261963
drosophila_melanogaster	ocm	FBGN0266083
caenorhabditis_elegans		WBGENE00003106
caenorhabditis_elegans		WBGENE00004750
caenorhabditis_elegans		WBGENE00006545
caenorhabditis_elegans		WBGENE00006546
caenorhabditis_elegans		WBGENE00006556
caenorhabditis_elegans		WBGENE00006557
caenorhabditis_elegans		WBGENE00006559
caenorhabditis_elegans		WBGENE00044798

Paralogs (16): TBX21 (ENSG00000073861), TBX5 (ENSG00000089225), TBX15 (ENSG00000092607), TBX18 (ENSG00000112837), TBX2 (ENSG00000121068), TBX4 (ENSG00000121075), TBX22 (ENSG00000122145), TBX3 (ENSG00000135111), TBR1 (ENSG00000136535), TBX19 (ENSG00000143178), TBX6 (ENSG00000149922), EOMES (ENSG00000163508), TBXT (ENSG00000164458), TBX20 (ENSG00000164532), TBX10 (ENSG00000167800), MGA (ENSG00000174197)

Protein

Protein identifiers

T-box transcription factor TBX1 — O43435 (reviewed: O43435)

Alternative names: Testis-specific T-box protein

All UniProt accessions (6): O43435, A0A3B3IS18, A0A7P0Z4A3, A0A8V8TR38, D9ZGG0, Q152R5

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that plays a key role in cardiovascular development by promoting pharyngeal arch segmentation during embryonic development. Also involved in craniofacial muscle development. Together with NKX2-5, acts as a regulator of asymmetric cardiac morphogenesis by promoting expression of PITX2. Acts upstream of TBX1 for the formation of the thymus and parathyroid glands from the third pharyngeal pouch. Required for hair follicle stem cell self-renewal. Binds to the palindromic T site 5’-TTCACACCTAGGTGTGAA-3’ DNA sequence.

Subunit / interactions. Binds DNA as a dimer. Interacts with DSCR6. Interacts with NKX2-5.

Subcellular location. Nucleus.

Disease relevance. Haploinsufficiency of the TBX1 gene is responsible for most of the physical malformations present in DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). DGS is characterized by the association of several malformations: hypoplastic thymus and parathyroid glands, congenital conotruncal cardiopathy, and a subtle but characteristic facial dysmorphology. VCFS is marked by the association of congenital conotruncal heart defects, cleft palate or velar insufficiency, facial dysmorpholgy and learning difficulties. It is now accepted that these two syndromes represent two forms of clinical expression of the same entity manifesting at different stages of life. DiGeorge syndrome (DGS) [MIM:188400] A congenital syndrome characterized by a wide spectrum of characteristics including parathyroid hypoplasia resulting in hypocalcemia, thymic hypoplasia resulting in T-cell immunodeficiency, defects in the outflow tract of the heart, and craniofacial anomalies. Disturbance of cervical neural crest migration into the derivatives of the pharyngeal arches and pouches can account for the phenotype. The disease is caused by variants affecting the gene represented in this entry. Velocardiofacial syndrome (VCFS) [MIM:192430] A syndrome characterized by abnormal pharyngeal arch development that results in defective development of the parathyroid glands, thymus, and conotruncal region of the heart. The phenotype is highly variable, with no single clinical feature present in every patient. Affected individuals may present with structural or functional palatal abnormalities, cardiac defects, unique facial characteristics, hypernasal speech, hypotonia, and defective thymic development associated with impaired immune function. In addition, affected individuals may present with learning disabilities, overt developmental delay, and psychiatric disorders. The disease is caused by variants affecting the gene represented in this entry. Conotruncal heart malformations (CTHM) [MIM:217095] A group of congenital heart defects involving the outflow tracts. Examples include truncus arteriosus communis, double-outlet right ventricle and transposition of great arteries. Truncus arteriosus communis is characterized by a single outflow tract instead of a separate aorta and pulmonary artery. In transposition of the great arteries, the aorta arises from the right ventricle and the pulmonary artery from the left ventricle. In double outlet of the right ventricle, both the pulmonary artery and aorta arise from the right ventricle. The disease is caused by variants affecting the gene represented in this entry. Tetralogy of Fallot (TOF) [MIM:187500] A congenital heart anomaly which consists of pulmonary stenosis, ventricular septal defect, dextroposition of the aorta (aorta is on the right side instead of the left) and hypertrophy of the right ventricle. In this condition, blood from both ventricles (oxygen-rich and oxygen-poor) is pumped into the body often causing cyanosis. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
O43435-1	A	yes
O43435-2	B
O43435-3	C, TBX1C

RefSeq proteins (4): NP_001366129, NP_005983, NP_542377, NP_542378 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001699	TF_T-box	Family
IPR008967	p53-like_TF_DNA-bd_sf	Homologous_superfamily
IPR018186	TF_T-box_CS	Conserved_site
IPR036960	T-box_sf	Homologous_superfamily
IPR046360	T-box_DNA-bd	Domain

Pfam: PF00907

UniProt features (31 total): strand 12, sequence variant 5, helix 5, compositionally biased region 3, splice variant 2, chain 1, DNA-binding region 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4A04	X-RAY DIFFRACTION	2.58

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43435-F1	70.15	0.46

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9733709	Cardiogenesis
R-HSA-1266738	Developmental Biology

MSigDB gene sets: 724 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_MYOTUBE_DIFFERENTIATION, MODULE_52, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_BODY_MORPHOGENESIS, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, MORF_FLT1, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_BEHAVIOR, GOBP_OUTFLOW_TRACT_SEPTUM_MORPHOGENESIS, GOBP_CORONARY_VASCULATURE_DEVELOPMENT, GOBP_REGULATION_OF_PHOSPHORYLATION

GO Biological Process (62): angiogenesis (GO:0001525), blood vessel development (GO:0001568), cell fate specification (GO:0001708), neural crest cell migration (GO:0001755), positive regulation of protein phosphorylation (GO:0001934), lymph vessel development (GO:0001945), positive regulation of mesenchymal cell proliferation (GO:0002053), heart morphogenesis (GO:0003007), outflow tract septum morphogenesis (GO:0003148), outflow tract morphogenesis (GO:0003151), regulation of transcription by RNA polymerase II (GO:0006357), determination of left/right symmetry (GO:0007368), pattern specification process (GO:0007389), mesoderm development (GO:0007498), heart development (GO:0007507), muscle organ development (GO:0007517), sensory perception of sound (GO:0007605), cell population proliferation (GO:0008283), positive regulation of cell population proliferation (GO:0008284), anterior/posterior pattern specification (GO:0009952), vagus nerve morphogenesis (GO:0021644), epithelial cell differentiation (GO:0030855), thyroid gland development (GO:0030878), somatic stem cell population maintenance (GO:0035019), social behavior (GO:0035176), aorta morphogenesis (GO:0035909), ear morphogenesis (GO:0042471), inner ear morphogenesis (GO:0042472), outer ear morphogenesis (GO:0042473), middle ear morphogenesis (GO:0042474), odontogenesis of dentin-containing tooth (GO:0042475), muscle cell fate commitment (GO:0042693), positive regulation of MAPK cascade (GO:0043410), tongue morphogenesis (GO:0043587), cellular response to fibroblast growth factor stimulus (GO:0044344), negative regulation of cell differentiation (GO:0045596), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), retinoic acid receptor signaling pathway (GO:0048384), blood vessel morphogenesis (GO:0048514)

GO Molecular Function (9): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA binding (GO:0003677), protein homodimerization activity (GO:0042803), sequence-specific DNA binding (GO:0043565), protein dimerization activity (GO:0046983), sequence-specific double-stranded DNA binding (GO:1990837), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
vasculature development	2
anatomical structure development	2
regulation of DNA-templated transcription	2
animal organ development	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cell fate commitment	1
cellular developmental process	1
neural crest cell development	1
mesenchymal cell migration	1
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
positive regulation of cell population proliferation	1
mesenchymal cell proliferation	1
regulation of mesenchymal cell proliferation	1
heart development	1
animal organ morphogenesis	1
outflow tract morphogenesis	1
cardiac septum morphogenesis	1
heart morphogenesis	1
anatomical structure morphogenesis	1
transcription by RNA polymerase II	1
determination of bilateral symmetry	1
left/right pattern formation	1
multicellular organism development	1
multicellular organismal process	1
tissue development	1
circulatory system development	1
muscle structure development	1
sensory perception of mechanical stimulus	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
regionalization	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1

Protein interactions and networks

STRING

1238 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TBX1	GNB1L	Q9BYB4	887
TBX1	CRKL	P46109	812
TBX1	TMEM26	Q6ZUK4	786
TBX1	NKX2-5	P52952	757
TBX1	SEPTIN5	Q99719	751
TBX1	PRODH	O43272	724
TBX1	GSC2	O15499	721
TBX1	DGCR6L	Q9BY27	705
TBX1	DGCR6	Q14129	705
TBX1	GP1BB	P13224	702
TBX1	COMT	P21964	701
TBX1	ISL1	P20663	688
TBX1	PRODH	O43272	682
TBX1	PITX2	Q99697	667
TBX1	HIRA	P54198	663

IntAct

6 interactions, top by confidence:

A	B	Type	Score
RIPPLY3	TBX1	psi-mi:“MI:0915”(physical association)	0.560
PIPSL	C1orf226	psi-mi:“MI:0914”(association)	0.350
RIPPLY3	A2ML1	psi-mi:“MI:0914”(association)	0.350
TLE1	TBX1	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): TBX1 (Affinity Capture-RNA), TBX1 (Affinity Capture-MS), TBX1 (Affinity Capture-MS), TBX1 (Affinity Capture-MS), RPL22 (Cross-Linking-MS (XL-MS)), NPM1 (Cross-Linking-MS (XL-MS)), HIST1H1C (Cross-Linking-MS (XL-MS)), HIST1H1D (Cross-Linking-MS (XL-MS)), HIST1H1E (Cross-Linking-MS (XL-MS)), TBX1 (Proximity Label-MS), TBX1 (Affinity Capture-MS), TBX1 (Affinity Capture-MS)

ESM2 similar proteins: A1YF56, A2AEV7, A6NCS4, A7Y7W2, D3ZJK7, E1BEA8, F1MUS9, O15534, O35973, O43435, O43638, O60248, O75333, O77728, O94983, O95935, O95947, P22736, P46099, P51666, P56261, P57082, P70325, P70327, Q03484, Q0V8F0, Q15744, Q497V6, Q5DTT2, Q61660, Q61663, Q63HR2, Q64731, Q66JL1, Q6PZD9, Q6ZQN5, Q80Y50, Q810F8, Q861Q9, Q8AV66

Diamond homologs: A1YF56, A2AWL7, D3ZJK7, E1BEA8, O01409, O13161, O15119, O15178, O17212, O43435, O54839, O60806, O70306, O73718, O75333, O95935, O95936, O95947, P20293, P24781, P55965, P56158, P57082, P70323, P70324, P70325, P70326, P70327, P79742, P79777, P79778, P79779, P79944, P80492, P87377, P90971, Q07998, Q13207, Q16650, Q17134

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ASH2L	“up-regulates activity”	TBX1	binding
TBX1	“up-regulates quantity by expression”	FLT4	“transcriptional regulation”
PITX2	“down-regulates quantity by repression”	TBX1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1196 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	46
Likely pathogenic	18
Uncertain significance	600
Likely benign	425
Benign	35

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1031062	NM_001379200.1(TBX1):c.1179_1180insAG (p.Leu394fs)	Pathogenic
1071027	NC_000022.10:g.(?19743226)(19755855_?)del	Pathogenic
1071028	NC_000022.10:g.(?19747167)(19754390_?)del	Pathogenic
1071029	NC_000022.10:g.(?_19748454)_19748649del	Pathogenic
1071222	NM_001379200.1(TBX1):c.1117del (p.Leu373fs)	Pathogenic
1354584	NM_001379200.1(TBX1):c.195_229del (p.Ala66fs)	Pathogenic
1378052	NM_001379200.1(TBX1):c.186C>A (p.Cys62Ter)	Pathogenic
1402928	NM_001379200.1(TBX1):c.794_798dup (p.Glu267fs)	Pathogenic
1432687	NM_001379200.1(TBX1):c.881del (p.Lys294fs)	Pathogenic
147498	GRCh38/hg38 22q11.21(chr22:18339130-21086225)x1	Pathogenic
1967408	NM_001379200.1(TBX1):c.199_227del (p.Pro67fs)	Pathogenic
2133191	NM_001379200.1(TBX1):c.201dup (p.Gly68fs)	Pathogenic
2764419	NM_001379200.1(TBX1):c.1206_1207insGAACCCCGAGC (p.Ser403fs)	Pathogenic
2769601	NM_001379200.1(TBX1):c.1027del (p.Thr343fs)	Pathogenic
2803732	NM_001379200.1(TBX1):c.1015C>T (p.Gln339Ter)	Pathogenic
280935	NM_001379200.1(TBX1):c.525_528dup (p.Lys177delinsArgTer)	Pathogenic
2848356	NM_001379200.1(TBX1):c.1252G>T (p.Glu418Ter)	Pathogenic
2866293	NM_001379200.1(TBX1):c.243del (p.Phe81fs)	Pathogenic
2917318	NM_001379200.1(TBX1):c.198_229dup (p.His77fs)	Pathogenic
3028918	NM_080647.1:g.(?19241636)(21349222_?)del	Pathogenic
3389752	NM_001379200.1(TBX1):c.364C>T (p.Gln122Ter)	Pathogenic
3706411	NM_001379200.1(TBX1):c.1036+2T>C	Pathogenic
373046	NM_001379200.1(TBX1):c.1203_1222dup (p.Glu408fs)	Pathogenic
3908075	NM_001379200.1(TBX1):c.652C>T (p.Gln218Ter)	Pathogenic
4075816	NM_080647.1(TBX1):c.3_27dup (p.Met10fs)	Pathogenic
424199	NM_001379200.1(TBX1):c.823G>T (p.Glu275Ter)	Pathogenic
4280099	NM_001379200.1:c.(?-130)(1488_?)dup	Pathogenic
4718072	NM_001379200.1(TBX1):c.1215dup (p.Asn406fs)	Pathogenic
4728536	NM_001379200.1(TBX1):c.1057G>T (p.Glu353Ter)	Pathogenic
4729263	NM_001379200.1(TBX1):c.1122_1144del (p.Val377fs)	Pathogenic

SpliceAI

1645 predictions. Top by Δscore:

Variant	Effect	Δscore
22:19763237:CCAG:C	acceptor_loss	1.0000
22:19763238:CA:C	acceptor_loss	1.0000
22:19763239:A:AG	acceptor_gain	1.0000
22:19763239:A:T	acceptor_loss	1.0000
22:19763239:AGGC:A	acceptor_gain	1.0000
22:19763240:G:GG	acceptor_gain	1.0000
22:19763240:GGCG:G	acceptor_gain	1.0000
22:19763340:CCG:C	donor_loss	1.0000
22:19763342:GG:G	donor_loss	1.0000
22:19763343:G:GG	donor_gain	1.0000
22:19763344:T:G	donor_loss	1.0000
22:19764322:GCCAC:G	donor_gain	1.0000
22:19764327:G:GG	donor_gain	1.0000
22:19764952:TTCCA:T	acceptor_loss	1.0000
22:19764954:CCA:C	acceptor_loss	1.0000
22:19764956:A:AG	acceptor_gain	1.0000
22:19764956:AGATT:A	acceptor_loss	1.0000
22:19764957:G:GG	acceptor_gain	1.0000
22:19764957:GATT:G	acceptor_gain	1.0000
22:19764957:GATTA:G	acceptor_gain	1.0000
22:19765110:TCGGG:T	donor_loss	1.0000
22:19765112:GG:G	donor_gain	1.0000
22:19765113:GG:G	donor_gain	1.0000
22:19765113:GGT:G	donor_loss	1.0000
22:19765115:T:A	donor_loss	1.0000
22:19757128:GCGA:G	donor_gain	0.9900
22:19759556:A:AG	acceptor_gain	0.9900
22:19759557:G:GG	acceptor_gain	0.9900
22:19759557:GC:G	acceptor_gain	0.9900
22:19762365:G:GT	donor_gain	0.9900

AlphaMissense

3268 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:19761211:T:A	L114Q	1.000
22:19761211:T:C	L114P	1.000
22:19761226:T:C	L119P	1.000
22:19761228:T:A	W120R	1.000
22:19761228:T:C	W120R	1.000
22:19761228:T:G	W120G	1.000
22:19761229:G:C	W120S	1.000
22:19761229:G:T	W120L	1.000
22:19761230:G:C	W120C	1.000
22:19761230:G:T	W120C	1.000
22:19761237:T:A	F123I	1.000
22:19761237:T:C	F123L	1.000
22:19761237:T:G	F123V	1.000
22:19761238:T:C	F123S	1.000
22:19761238:T:G	F123C	1.000
22:19761239:C:A	F123L	1.000
22:19761239:C:G	F123L	1.000
22:19761247:T:C	L126P	1.000
22:19761249:G:C	G127R	1.000
22:19761250:G:T	G127V	1.000
22:19761253:C:T	T128I	1.000
22:19761255:G:A	E129K	1.000
22:19761255:G:C	E129Q	1.000
22:19761256:A:C	E129A	1.000
22:19761256:A:G	E129G	1.000
22:19761256:A:T	E129V	1.000
22:19761257:G:C	E129D	1.000
22:19761257:G:T	E129D	1.000
22:19761258:A:G	M130V	1.000
22:19761259:T:A	M130K	1.000

dbSNP variants (sampled 300 via entrez): RS1000115486 (22:19757558 G>A,C), RS1000148878 (22:19756630 C>T), RS1000161978 (22:19763178 C>T), RS1000182999 (22:19758528 G>A), RS1000263962 (22:19756463 C>G), RS1000275590 (22:19762940 G>A), RS1000356021 (22:19768746 A>G), RS1000520687 (22:19765620 G>A), RS1000551256 (22:19757338 C>T), RS1000741741 (22:19760821 G>A), RS1000882476 (22:19772288 A>C), RS1001038610 (22:19777322 G>A), RS1001082054 (22:19783442 C>T), RS1001212032 (22:19770951 C>T), RS1001282910 (22:19774063 GGAT>G,GGATGAT)

Disease associations

OMIM: gene MIM:602054 | disease phenotypes: MIM:188400, MIM:187500, MIM:192430, MIM:217095, MIM:616649, MIM:241550, MIM:148050

GenCC curated gene-disease

Disease	Classification	Inheritance
conotruncal heart malformations	Definitive	Autosomal dominant
DiGeorge syndrome	Definitive	Autosomal dominant
velocardiofacial syndrome	Strong	Autosomal dominant
22q11.2 deletion syndrome	Supportive	Autosomal dominant

Mondo (9): DiGeorge syndrome (MONDO:0008564), tetralogy of fallot (MONDO:0008542), velocardiofacial syndrome (MONDO:0008644), conotruncal heart malformations (MONDO:0016581), hypertrophic cardiomyopathy (MONDO:0005045), hereditary spherocytosis type 2 (MONDO:0000913), hypoplastic left heart syndrome (MONDO:0004933), KBG syndrome (MONDO:0007846), 22q11.2 deletion syndrome (MONDO:0018923)

Orphanet (9): 22q11.2 deletion syndrome (Orphanet:567), Conotruncal heart malformations (Orphanet:2445), Tetralogy of Fallot (Orphanet:3303), Common arterial trunk (Orphanet:3384), Double outlet right ventricle (Orphanet:3426), Rare hypertrophic cardiomyopathy (Orphanet:217569), Hereditary spherocytosis (Orphanet:822), Hypoplastic left heart syndrome (Orphanet:2248), KBG syndrome (Orphanet:2332)

HPO phenotypes

218 total (30 of 218 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000034	Hydrocele testis
HP:0000047	Hypospadias
HP:0000076	Vesicoureteral reflux
HP:0000083	Renal insufficiency
HP:0000089	Renal hypoplasia
HP:0000110	Renal dysplasia
HP:0000113	Polycystic kidney dysplasia
HP:0000122	Unilateral renal agenesis
HP:0000126	Hydronephrosis
HP:0000130	Abnormality of the uterus
HP:0000138	Ovarian cyst
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000193	Bifid uvula
HP:0000194	Open mouth
HP:0000201	Pierre-Robin sequence
HP:0000218	High palate
HP:0000220	Velopharyngeal insufficiency
HP:0000233	Thin vermilion border
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000262	Turricephaly
HP:0000268	Dolichocephaly
HP:0000272	Malar flattening

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002057_6	DNA methylation (parent-of-origin)	6.000000e-08
GCST002606_25	Prostate cancer	2.000000e-07
GCST002606_7	Prostate cancer	2.000000e-08
GCST003050_26	Schizophrenia	1.000000e-07
GCST003656_2	Acute kidney injury in critical illness	7.000000e-07
GCST003991_1	Childhood ear infection	1.000000e-19
GCST003995_36	Tonsillectomy	5.000000e-08
GCST005013_3	Childhood ear infection	1.000000e-19
GCST005014_164	Tonsillectomy	5.000000e-08
GCST005015_17	Myringotomy	3.000000e-10
GCST006102_6	Interleukin-10 levels	4.000000e-09
GCST007843_31	Rheumatoid arthritis	4.000000e-08
GCST008789_4	Adolescent idiopathic scoliosis	3.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0022599	DNA methylation
EFO:0007904	susceptibility to childhood ear infection measurement
EFO:0007924	tonsillectomy risk measurement
EFO:0004750	interleukin 10 measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D004062	DiGeorge Syndrome	C05.660.207.103.500; C14.240.400.021.500; C14.280.400.044.500; C15.604.451.249.500; C16.131.077.019.500; C16.131.240.400.021.500; C16.131.260.019.500; C16.131.482.249.500; C16.131.621.207.103.500; C16.320.180.019.500; C19.642.482.500.500
D018636	Hypoplastic Left Heart Syndrome	C14.240.400.625; C14.280.400.625; C16.131.240.400.625
D013771	Tetralogy of Fallot	C14.240.400.849; C14.280.400.849; C16.131.240.400.849
C537015	KBG syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects methylation, affects cotreatment, decreases methylation	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Tretinoin	increases expression, decreases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	increases phosphorylation	1
testosterone enanthate	affects expression	1
sulforaphane	decreases expression	1
vanadyl sulfate	decreases expression	1
abrine	decreases expression	1
bisphenol S	decreases expression	1
NSC 689534	affects binding, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	increases abundance, increases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Cadmium	increases abundance, decreases expression	1
Copper	affects binding, decreases expression	1
Hydrogen Peroxide	affects expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Selenomethionine	affects expression	1
Silicon Dioxide	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1
Acrylamide	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_WU87	YAHKMUi001-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

116 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00768820	PHASE4	RECRUITING	The Psychiatric and Cognitive Phenotypes in Velocardiofacial Syndrome
NCT01971593	PHASE4	TERMINATED	The Effects of Eplerenone on Markers of Myocardial Fibrosis in Adult Congenital Heart Disease
NCT00395538	PHASE3	TERMINATED	Effects of PTH Replacement on Bone in Hypoparathyroidism
NCT00564993	PHASE3	TERMINATED	Cardiac Function Under Stress for Early Detection of the Right Ventricular Insufficiency After Repair of Tetralogy of Fallot
NCT05290493	PHASE2	COMPLETED	NB-001 in Children and Adolescents With 22q11 Deletion Syndrome
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT00576407	PHASE2	COMPLETED	Thymus Transplantation in DiGeorge Syndrome #668
NCT00576836	PHASE2	COMPLETED	Thymus Transplantation Dose in DiGeorge #932
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT05149898	PHASE2	COMPLETED	Open-Label Study of ZYN002 Administered as a Transdermal Gel to Children and Adolescents With 22q11.2 Deletion Syndrome (INSPIRE)
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00848393	PHASE2	COMPLETED	Measures to Lower the Stress Response in Pediatric Cardiac Surgery
NCT02010905	PHASE2	UNKNOWN	Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-angiotensin-aldosterone System
NCT00566488	PHASE1	COMPLETED	Parathyroid and Thymus Transplantation in DiGeorge #931
NCT00579709	PHASE1	COMPLETED	Thymus Transplantation With Immunosuppression
NCT02895906	PHASE1	COMPLETED	Safety and Efficacy Study of NFC-1 in Subjects Aged 12-17 Years With 22q11.2DS & Associated Neuropsychiatric Conditions
NCT00849888	PHASE1	TERMINATED	Serum-Free Thymus Transplantation in DiGeorge Anomaly
NCT00573066	PHASE1	COMPLETED	Understanding Dexmedetomidine In Infants Post-Operative From Cardiac Surgery
NCT01915277	PHASE1	COMPLETED	A Phase I Study of Dexmedetomidine Bolus and Infusion in Corrective Infant Cardiac Surgery: Safety and Pharmacokinetics
NCT04713657	PHASE1	RECRUITING	Beta-blocker Administration for Cardiomyocyte Division
NCT02070211	PHASE2/PHASE3	UNKNOWN	Indicated Prevention With Long-chain Polyunsaturated Omega-3 Fatty Acids in Patients With 22q11 Microdeletion Syndrome.
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT00005102	Not specified	UNKNOWN	Immunologic Evaluation in Patients With DiGeorge Syndrome or Velocardiofacial Syndrome
NCT00105274	Not specified	COMPLETED	Velocardiofacial (VCFS; 22q11.2; DiGeorge) Syndrome Study
NCT00917189	Not specified	COMPLETED	Computerized Cognitive Skills Training for Adolescents With Velocardiofacial Syndrome
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT05664412	Not specified	RECRUITING	Using Transcranial Alternating Current Stimulation to Improve Executive Function in 22q11.2 Deletion Syndrome
NCT05849441	Not specified	COMPLETED	Mindfulness Program for Adolescents With 22q11DS
NCT00004361	Not specified	COMPLETED	Study of the Relationship Between Calcium Levels and Intact Parathyroid Hormone (iPTH) in Adults With Repaired or Palliated Conotruncal Cardiac Defects
NCT01460316	Not specified	COMPLETED	Conotruncal Cardiac Defects and Nutrigenetic Etiopathogeny
NCT00161109	Not specified	UNKNOWN	Genetics and Psychopathology in the 22q11 Deletion Syndrome
NCT00278005	Not specified	TERMINATED	Infection in DiGeorge Following CHD Surgery
NCT00556530	Not specified	RECRUITING	Examining Genetic Factors That Affect the Severity of 22q11.2 Deletion Syndrome
NCT00916955	Not specified	COMPLETED	Genetic Modifiers for 22q11.2 Syndrome
NCT01220531	Not specified	COMPLETED	Thymus Transplantation Safety-Efficacy
NCT01781923	Not specified	COMPLETED	Cognitive Remediation in 22q11DS
NCT02430584	Not specified	UNKNOWN	Whole Blood Specimen Collection From Pregnant Subjects
NCT02460328	Not specified	COMPLETED	Resolution of Primary Immune Defect in 22q11.2 Deletion Syndrome
NCT02787486	Not specified	COMPLETED	Expanded Noninvasive Genomic Medical Assessment: The Enigma Study