Definition: DiGeorge syndrome is mainly caused by a multigene, heterozygous, interstitial chromosomal deletion. Of the approximately 30 deleted genes, Tbx1 is the only gene that, after an extensive functional analysis in the mouse, has been found to be haploinsufficient.
The mutant phenotype is convincingly similar to the human syndrome, and its human homolog, TBX1, is the only gene for which mutations have been found in some patients without the chromosomal deletion. Tbx1 is an excellent tool to probe the genetic network governing embryonic pharyngeal development.
This syndrome is the most typical developmental defect of the embryonic pharyngeal system: a transient, vertebrate-specific structure that contributes to diverse tissues of the head, neck and thorax. Many birth defects, including a large fraction of congenital heart disease cases, derive from developmental problems of the pharyngeal system.
Del22q11.2 is an interstitial deletion of chromosome 22 associated with a characteristic phenotype clinically recognizable as DiGeorge syndrome, velocardiofacial syndrome or conotruncal anomaly face, which are collectively referred to as 22q11.2 deletion syndromes (22q11.2DS).
There are actually several versions of this deletion and the most common version eliminates 3 Mb of genomic DNA, including approximately 30 genes; smaller deletions are associated with essentially identical phenotypes.
It is still, therefore, uncertain whether 22q11.2DS is a contiguous gene deletion syndrome (i.e. a syndrome in which the deletion of different genes contributes to different aspects of the phenotype).
Del22q11 is the multigene deletion most commonly associated with phenotypic abnormalities (1:4000 live births) and it is an important cause of birth defects, including congenital heart disease and learning and psychiatric disorders.
Synopsis
craniofacial anomalies
- micrognathia
- low-set ears
- abnormal folded pinna
- middle ear abnormalities
- hypertelorism
- short palpebral fissures
- blunted nose
- short philtrum
- high arched palate
- cleft palate
- bifid uvula
thymic aplasia (thymic agenesis)
parathyroid anomales
- parathyroid hypoplasia
- parathyroid agenesis (aparathyroid aplasia)
accessory thyroid tissue
cardiovascular anomalies
- ventricular septal defect
- patent ductus arteriosus
- conotruncal defects
- interrupted aortic arch
- transposition of the great arteries (7801879)
- truncus arteriosus
- tetralogy of Fallot
- posterior malalignment type ventricular septal defect
- anomalous origin of the left main pulmonary artery from the ascending aorta (7778565)
- Right aortic arch
vascular anomalies
- pulmonary arterial aneurysm
- left common carotid artery arising from the pulmonary artery (8774335)
- vascular disruptions
- symbrachydactyly (9457506)
- microgyria in the distribution of the middle cerebral artery (9120232)
digestive
- esophageal atresia and tracheo-esophageal fistula (12891520)
- jejunal atresia
- abdominal lymphatic dysplasia (10191431)
abnormal growth of the thyroid cartilage (3822935)
laryngeal atresia
upper limb malformations
Associations
hepatoblastoma (14692228)
renal-cell carcinoma (14692228)
Etiology
contiguous gene syndrome involving deletion of the DiGeorge syndrome chromosome region (DGCR) involving mutations in TUP-like enhancer of split 1 (TUPLE1) (MIM.600237) and DiGeorge critical region gene 2 (DGCR2) (MIM.600594)
deletion of the 22q11.2 region
germline mutation in the TBX1 gene (MIM.602054)
References
Wurdak H, Ittner LM, Sommer L. DiGeorge syndrome and pharyngeal apparatus development. Bioessays. 2006 Nov;28(11):1078-86. PMID: 17041894
Vitelli F, Baldini A. Generating and modifying DiGeorge syndrome-like phenotypes in model organisms: is there a common genetic pathway? Trends Genet. 2003 Nov;19(11):588-93. PMID: 14585606
Yamagishi H, Srivastava D. Unraveling the genetic and developmental mysteries of 22q11 deletion syndrome. Trends Mol Med. 2003 Sep;9(9):383-9. PMID: 13129704
Baldini A. DiGeorge syndrome: the use of model organisms to dissect complex genetics. Hum Mol Genet. 2002 Oct 1;11(20):2363-9. PMID: 12351571
Lindsay EA. Chromosomal microdeletions: dissecting del22q11 syndrome. Nat Rev Genet. 2001 Nov;2(11):858-68. PMID: 11715041
Botta A, Amati F, Novelli G. Causes of the phenotype-genotype dissociation in DiGeorge syndrome: clues from mouse models. Trends Genet. 2001 Oct;17(10):551-4. PMID: 11585644
Epstein JA. Developing models of DiGeorge syndrome. Trends Genet. 2001 Oct;17(10):S13-7. PMID: 11585671
Scambler PJ. The 22q11 deletion syndromes. Hum Mol Genet. 2000 Oct;9(16):2421-6. PMID: 11005797