22q11 Deletion Syndrome: A Role for Tbx1 in Pharynx and Cardiovascular Development


DiGeorge and velocardiofacial syndromes result from a chromosomal deletion involving proximal chromosome 22 and affected individuals commonly present with congenital heart defects, feeding problems, speech delay and learning problems. Psychiatric illness may present later in life. Mutation analysis and creation of mouse models which mimic the human disorder have identified that the Tbx1 (T‐box 1) transcription factor is the major dosage‐sensitive gene in the deletion region and have allowed exploration of the underlying developmental pathways and signalling networks disrupted in these syndromes. Of particular importance in this regard are Fgf (fibroblast growth factor) and retinoic acid signalling. Tbx1 is in genetic epistasis with loci encoding several transcription factors and signalling molecules, providing some rationale for the very variable clinical presentation. Gain‐of‐function, or duplications containing Tbx1, is also associated with heart defect.

Key Concepts:

  • The presence of a dominant phenotype secondary to gene hemizygosity is called haploinsufficiency.

  • Genetic epistasis is the phenomenon where the effects of one gene are modified by one or several other genes, which are called modifier genes.

  • Each pharyngeal arch surrounds an arch artery that connects the heart, by means of the aortic sac, to the dorsal aortae.

  • The neural crest is a pluripotent embryonic neuroectodermal cell population that migrates extensively and differentiates into diverse structures such as the face, neck, heart, adrenal gland, peripheral nervous system and skin.

  • Low copy number repeat are 1–400 kb blocks of genomic sequence that are duplicated in one or more locations on a chromosome and can act as substrates for aberrant recombination events.

Keywords: Tbx1; DiGeorge syndrome; velocardiofacial syndrome; conotruncal anomaly face syndrome

Figure 1.

Schematic comparing gene order in 22q11 with subcentromeric mouse chromosome 16. The arrows indicate the deletions of the Df1 mouse strain and typical human DiGeorge syndrome patient. Not all genes are represented, not all synonyms are used and physical distances are not to scale.

Figure 2.

The pharyngeal apparatus. (a) Side and frontal views of E10.5 Tbx1+/− embryo stained for LacZ. Tbx1 expressing domains are highlighted in blue and covered a large portion of the pharyngeal apparatus. (b) Schematic view of the pharyngeal apparatus at E10.5. It is composed of (PAs) and pouches. Each pharyngeal arch surrounds an arch artery (PAA) that connects the heart by means of the aortic sac, to the dorsal aortae. Tbx1 is expressed in the ectoderm, mesoderm and endoderm but not in the neural crest cell lineage of the pharyngeal apparatus. Ov. and dotted circle, otic vesicle. Adapted from Scambler , with permission from Springer.

Figure 3.

Tbx1 interaction summary. Tbx1 expression is negatively regulated by retinoic acid and Wnt‐β‐catenin signalling, and positively regulated by Shh and Chordin. Tbx1 has been shown to physically interact with both Srf and Smad1, which modulate its transcriptional activity. Expression and microarray studies have revealed a number of genes that have reduced expression in various tissues. Some of these genes (highlighted in different colours) interact with Tbx1, such that double heterozygote mouse embryos have a more severe/penetrant phenotype.



Arnold JS, Werling U, Braunstein EM et al. (2006) Inactivation of Tbx1 in the pharyngeal endoderm results in 22q11DS malformations. Development 133: 977–987.

Bachiller D, Klingensmith J, Shneyder N et al. (2003) The role of chordin/Bmp signals in mammalian pharyngeal development and DiGeorge syndrome. Development 130: 3567–3578.

Bergman A and Blennow E (2000) Inv dup(22), del(22)(q11) and r(22) in the father of a child with DiGeorge syndrome. European Journal of Human Genetics 8: 801–804.

Brown CB, Wenning JM, Lu MM et al. (2004) Cre‐mediated excision of Fgf8 in the Tbx1 expression domain reveals a critical role for Fgf8 in cardiovascular development in the mouse. Developmental Biology 267: 190–202.

Calmont A, Ivins S, Van Bueren KL et al. (2009) Tbx1 controls cardiac neural crest cell migration during arch artery development by regulating Gbx2 expression in the pharyngeal ectoderm. Development 136: 3173–3183.

Carey AH, Kelly D, Halford S et al. (1992) Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome. American Journal of Human Genetics 51: 964–970.

Chen L, Fulcoli FG, Tang S and Baldini A (2009) Tbx1 regulates proliferation and differentiation of multipotent heart progenitors. Circulation Research 105: 842–851.

Chen L, Mupo A, Huynh T et al. (2010) Tbx1 regulates Vegfr3 and is required for lymphatic vessel development. Journal of Cell Biology 189: 417–424.

DeRuiter MC, Poelmann RE, Mentink MM, Vaniperen L and Gittenberger‐de Groot AC (1993) Early formation of the vascular system in quail embryos. Anatomical Record 235: 261–274.

DiGeorge AM (1965) Discussion. Journal of Pediatrics 67: 907.

Du Montcel ST, Mendizabal H, Ayme S, Levy A and Philip N (1996) Prevalence of 22q11 microdeletion. Journal of Medical Genetics 33: 719.

Edelmann L, Pandita R, Spiteri E et al. (1999) A common molecular basis for rearrangement disorders on chromosome 22q11. Human Molecular Genetics 8: 1157–1167.

Frank DU, Fotheringham LK, Brewer JA et al. (2002) An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome. Development 129: 4591–4603.

Fulcoli FG, Huynh T, Scambler PJ and Baldini A (2009) Tbx1 regulates the BMP‐Smad1 pathway in a transcription independent manner. PLoS ONE 4: e6049.

Goodship J, Cross I, Scambler P and Burn J (1995) Monozygotic twins with chromosome 22q11 deletion and discordant phenotype. Journal of Medical Genetics 32: 746–748.

Gothelf D, Schaer M and Eliez S (2008) Genes, brain development and psychiatric phenotypes in velo‐cardio‐facial syndrome. Developmental Disabilities Research Reviews 14: 59–68.

Halford S, Lindsay E, Nayudu M et al. (1993) Low‐copy‐repeat sequences flank the DiGeorge/velo‐cardio‐facial syndrome loci at 22q11. Human Molecular Genetics 2: 191–196.

Huh SH and Ornitz DM (2010) Beta‐catenin deficiency causes DiGeorge syndrome‐like phenotypes through regulation of Tbx1. Development 137: 1137–1147.

Ivins S, van Lammerts BK, Roberts C et al. (2005) Microarray analysis detects differentially expressed genes in the pharyngeal region of mice lacking Tbx1. Developmental Biology 285: 554–569.

Jerome LA and Papaioannou VE (2001) DiGeorge syndrome phenotype in mice mutant for the T‐box gene, Tbx1. Nature Genetics 27: 286–291.

Kelly RG and Papaioannou VE (2007) Visualization of outflow tract development in the absence of Tbx1 using an FgF10 enhancer trap transgene. Developmental Dynamics 236: 821–828.

Lewin MB, Lindsay EA, Jurecic V et al. (1997) A genetic etiology for interruption of the aortic arch type B. American Journal of Cardiology 80: 493–497.

Liao J, Aggarwal VS, Nowotschin S et al. (2008) Identification of downstream genetic pathways of Tbx1 in the second heart field. Developmental Biology 316: 524–537.

Liao J, Kochilas L, Nowotschin S et al. (2004) Full spectrum of malformations in velo‐cardio‐facial syndrome/DiGeorge syndrome mouse models by altering Tbx1 dosage. Human Molecular Genetics 13: 1577–1585.

Lindsay EA, Vitelli F, Su H et al. (2001) Tbx1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410: 97–101.

Merscher S, Funke B, Epstein JA et al. (2001) TBX1 is responsible for cardiovascular defects in velo‐cardio‐facial/DiGeorge syndrome. Cell 104: 619–629.

Moon AM, Guris DL, Seo JH et al. (2006) Crkl deficiency disrupts Fgf8 signaling in a mouse model of 22q11 deletion syndromes. Developmental Cell 10: 71–80.

Murphy KC (2002) Schizophrenia and velo‐cardio‐facial syndrome. Lancet 359: 426–430.

Nowotschin S, Liao J, Gage PJ et al. (2006) Tbx1 affects asymmetric cardiac morphogenesis by regulating Pitx2 in the secondary heart field. Development 133: 1565–1573.

Paylor R, Glaser B, Mupo A et al. (2006) Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome. Proceedings of the National Academy of Sciences of the USA 103: 7729–7734.

Prasad SE, Howley S and Murphy KC (2008) Candidate genes and the behavioral phenotype in 22q11.2 deletion syndrome. Developmental Disabilities Research Reviews 14: 26–34.

Randall V, McCue K, Roberts C et al. (2009) Great vessel development requires biallelic expression of Chd7 and Tbx1 in pharyngeal ectoderm in mice. Journal of Clinical Investigation 119: 3301–3310.

Roberts C, Ivins S, Cook AC, Baldini A and Scambler PJ (2006) Cyp26 genes a1, b1 and c1 are down‐regulated in Tbx1 null mice and inhibition of Cyp26 enzyme function produces a phenocopy of DiGeorge Syndrome in the chick. Human Molecular Genetics 15: 3394–3410.

Roberts C, Ivins SM, James CT and Scambler PJ (2005) Retinoic acid down‐regulates Tbx1 expression in vivo and in vitro. Developmental Dynamics 232: 928–938.

Ryan AK, Goodship JA, Wilson DI et al. (1997) Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. Journal of Medical Genetics 34: 798–804.

Ryckebusch L, Bertrand N, Mesbah K et al. (2010) Decreased levels of embryonic retinoic acid synthesis accelerate recovery from arterial growth delay in a mouse model of DiGeorge syndrome. Circulation Research 106: 686–694.

Scambler PJ (2000) The 22q11 deletion syndromes. Human Molecular Genetics 9: 2421–2426.

Scambler P (2010) 22q11 deletion syndrome: a role for TBX1 in pharyngeal and cardiovascular development. Pediatric Cardiology 31: 378–390.

Shaikh TH, Kurahashi H and Emanuel BS (2001) Evolutionarily conserved low copy repeats (LCRs) in 22q11 mediate deletions, duplications, translocations, and genomic instability: an update and literature review. Genetics in Medicine 3: 6–13.

Shprintzen RJ (2008) Velo‐cardio‐facial syndrome: 30 Years of study. Developmental Disabilities Research Reviews 14: 3–10.

Van Bueren KL, Papangeli I, Rochais F et al. (2010) Hes1 expression is reduced in Tbx1 null cells and is required for the development of structures affected in 22q11 deletion syndrome. Developmental Biology 340: 369–380.

Wilson DI, Cross IE, Wren C et al. (1994) Minimum prevalence of chromosome 22q11 deletions. American Journal of Human Genetics 55: A169 [Ref Type: Abstract].

Xu H, Cerrato F and Baldini A (2005) Timed mutation and cell‐fate mapping reveal reiterated roles of Tbx1 during embryogenesis, and a crucial function during segmentation of the pharyngeal system via regulation of endoderm expansion. Development 132: 4387–4395.

Yagi H, Furutani Y, Hamada H et al. (2003) Role of TBX1 in human del22q11.2 syndrome. Lancet 362: 1366–1373.

Yamagishi H, Maeda J, Hu T et al. (2003) Tbx1 is regulated by tissue‐specific forkhead proteins through a common Sonic hedgehog‐responsive enhancer. Genes & Development 17: 269–281.

Zhang Z and Baldini A (2008) In vivo response to high‐resolution variation of Tbx1 mRNA dosage. Human Molecular Genetics 17: 150–157.

Zhang Z, Cerrato F, Xu H et al. (2005) Tbx1 expression in pharyngeal epithelia is necessary for pharyngeal arch artery development. Development 132: 5307–5315.

Zhang Z, Huynh T and Baldini A (2006) Mesodermal expression of Tbx1 is necessary and sufficient for pharyngeal arch and cardiac outflow tract development. Development 133: 3587–3595.

Zweier C, Sticht H, ydin‐Yaylagul I, Campbell CE and Rauch A (2007) Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions. American Journal of Human Genetics 80: 510–517.

Further Reading

Emanuel BS, Budarf BS and Scambler PJ (1998) The genetic basis of conotruncal heart defects: the chromosome 22q11.2 deletion. In: Rosenthal N and Harvey R (eds) Heart Development, pp. 463–478. New York: Academic Press.

Graham A and Smith A (2001) Patterning the pharyngeal arches. BioEssays 23: 54–61.

Lindsay EA (2001) Chromosome microdeletions: dissecting del22q11 syndrome. Nature Reviews. Genetics 2: 858–868.

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Calmont, Amelie, and Scambler, Peter(Sep 2010) 22q11 Deletion Syndrome: A Role for Tbx1 in Pharynx and Cardiovascular Development. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006074.pub2]