TBX1

Chr 22AD

T-box transcription factor 1

Also known as: CAFS, CATCH22, CTHM, DGCR, DGS, DORV, TBX1C, TGA

NCBI Gene: 6899 ENSG00000184058 UniProt: O43435 OMIM: 602054

TBX1 encodes a transcription factor that regulates developmental processes, particularly those involving neural crest cell development. Haploinsufficiency causes DiGeorge syndrome/velocardiofacial syndrome and related 22q11.2 deletion phenotypes including conotruncal heart defects and tetralogy of Fallot through autosomal dominant inheritance. Loss-of-function mutations disrupt normal transcriptional regulation of genes critical for pharyngeal arch and cardiac outflow tract development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.434 OMIM phenotypes

Clinical Summary— TBX1

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.84) — some intolerance to loss-of-function variants.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.43LOEUF

pLI 0.837

Z-score 3.07

OE 0.14 (0.05–0.43)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.74Z-score

OE missense 0.86 (0.76–0.97)

189 obs / 219.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.14 (0.05–0.43)

0≤0.351.4

Missense OE?0.86 (0.76–0.97)

0≤0.61.4

Synonymous OE?1.46

0≤1.21.6

LoF obs/exp: 2 / 14.7Missense obs/exp: 189 / 219.7Syn Z: -3.55

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTBX1-related 22q11.2 deletion syndromeLOFAD

This gene — mechanism propensity

0.3892th %ile

GOF

0.3590th %ile

LOF

0.79top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.43

GOF1 literature citation

Literature Evidence

GOFWe report a novel heterozygous missense mutation, H194Q, in a familial case of Shprintzen syndrome and show that this and the two previously reported missense mutations result in gain of function, possibly through stabilization of the protein dimer DNA complex. We therefore conclude that TBX1 gain-o1

LOFTbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References