TBX1 – DiGeorge syndrome

TBX1, a T-box transcription factor encoded on chromosome 22q11.2, is the key dosage-sensitive gene implicated in DiGeorge syndrome (DGS). Haploinsufficiency of TBX1 underlies the core features of DGS/velocardiofacial syndrome, including hypoparathyroidism, thymic hypoplasia, and conotruncal heart defects, as originally demonstrated by mapping and cloning studies comparing human and mouse orthologs (PMID:9268629).

Multiple non-deletion heterozygous TBX1 mutations have been identified in DGS patients lacking the canonical 22q11.2 deletion. A familial exon 9C frameshift, c.1158_1159delinsT (p.Gly387AlafsTer73), segregated with hypoparathyroidism, deafness, and facial asymmetry in a kindred of four affected individuals (PMID:32110744). Independent studies reported de novo and inherited truncating variants—c.1117del (p.Leu373fs) and c.1063C>T (p.Gln355Ter)—abrogating a novel C-terminal nuclear localization signal (PMID:15703190), as well as gain-of-function missense changes (c.609C>G (p.His203Gln) and c.470T>A (p.Phe157Tyr)) producing similar DGS phenotypes (PMID:17273972). An in-frame deletion, c.173_229del (p.Arg58_Pro76del), was also identified in non-syndromic tetralogy of Fallot, demonstrating the broader cardiac impact of TBX1 variants (PMID:20937753). In total, at least eight unrelated probands and one multigenerational family have confirmed TBX1 mutation–DGS associations.

Inheritance of TBX1-related DGS is autosomal dominant via haploinsufficiency or dominant-negative mechanisms. Variant spectrum includes frameshift, nonsense, missense and small in-frame deletions. Recurrent or founder alleles have not been reported; all pathogenic variants are private or de novo.

Functional studies in mouse models and cellular assays corroborate TBX1’s developmental role. Ablation of Tbx1 recapitulates DGS-like cardiac outflow and pharyngeal arch defects; deletion of the C-terminal nuclear localization signal by 1223delC impairs nuclear import and transcriptional activity, confirming loss-of-function (PMID:15703190). Tbx1 interacts genetically with Fgf8 in pharyngeal arch artery development (PMID:12223416), while pharmacologic or genetic suppression of p53 partially rescues cardiovascular anomalies in Tbx1-haploinsufficient embryos, highlighting epigenetic regulation via H3K27me3 at the Gbx2 locus (PMID:25197075). Genome-wide SELEX identified a tandem T-site repeat consensus for TBX1 binding, and reporter assays confirmed regulation of developmental genes including Fgf8 and Bmper (PMID:24797903).

Conflicting evidence arises from early studies of isolated conotruncal defects without DGS features, where no TBX1 coding mutations were found, suggesting genetic modifiers or alternative loci contribute to phenotypic variability (PMID:12700609).

Integration of genetic and experimental data establishes a strong gene-disease relationship: TBX1 haploinsufficiency or gain-of-function perturbations cause the DGS spectrum, with clear mechanistic insights into pharyngeal and cardiovascular development. Additional rare modifiers likely modulate expressivity but do not detract from TBX1’s primary etiologic role. Key take-home: TBX1 sequencing should be considered in deletion-negative DGS patients to inform diagnosis, anticipate complications, and guide genetic counseling.

References

• Genomics • 1997 • Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Tbx1 gene PMID:9268629
• Human molecular genetics • 2005 • Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation PMID:15703190
• American journal of human genetics • 2007 • Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions PMID:17273972
• Heart (British Cardiac Society) • 2010 • Systematic survey of variants in TBX1 in non-syndromic tetralogy of Fallot identifies a novel 57 base pair deletion that reduces transcriptional activity but finds no evidence for association with common variants PMID:20937753
• Development (Cambridge, England) • 2002 • A genetic link between Tbx1 and fibroblast growth factor signaling PMID:12223416
• Proceedings of the National Academy of Sciences • 2014 • p53 Suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome PMID:25197075
• PLoS One • 2014 • Mammalian TBX1 preferentially binds and regulates downstream targets via a tandem T-site repeat PMID:24797903
• European journal of human genetics • 2003 • DiGeorge subtypes of nonsyndromic conotruncal defects: evidence against a major role of TBX1 gene PMID:12700609

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