DiGeorge TBX1 / 22q13.3 Combination LPU014 - Detail

DiGeorge Syndrome

DiGeorge syndrome¹ and a variety of congenital malformation syndromes, including Velocardiofacial (VCFS) ² and Conotruncal Anomaly Face syndromes³ share the phenotypic features covered by the acronym CATCH22 (cardiac defects; abnormal facies; thymic hypoplasia; cleft palate; hypocalcaemia) and deletion of chromosome 22 at 22q11.2^4,5,6. In addition around 17% of nonsyndromic patients with isolated conotruncal defects have been shown to have a 22q11.2 microdeletion⁷. The incidence of these anomalies is estimated to be 1:4000 live births⁸ and therefore the deletion 22q11.2 represents one of the most common genetic defects.

A region of 2 Mb referred to as the DiGeorge Critical Region (DGCR) is most commonly deleted in up to 90% of patients^5,9,10. Within the DGCR a minimal critical region of 480-575 kb has been described^11,12 containing several genes including the T-box transcription factor -TBX1, a key candidate for the aortic arch malformations and anomalies related to pharyngeal apparatus and ear development seen in DGS^13,14,15. In addition, TBX1 may play a role in behaviour¹⁶. About 35% patients with DiGeorge develop psychiatric disorders, mainly schizophrenia and bipolar disorder.

22q13.3 deletion syndrome

The 22q13.3 deletion syndrome presents a recognisable phenotype characterised by hypotonia, delay or absence of expressive speech, moderate to profound mental retardation, normal to accelerated growth and mild dysmorphic features. ¹⁷ Some deletions of the terminal region of chromosome 22q are cytogenetically visible. However, a few cases of cryptic deletions have been reported, ^17,18 suggesting that the actual incidence of 22q telomere deletion may be higher than previously thought.

Several observations of patients with 22q13.3 deletion showed that the ProSAP2/SHANK3 ²⁴ gene, coding for a structural protein of the postsynaptic density of excitation synapses and expressed in the cortex and cerebellum of the brain¹⁹, was disrupted ^19,20,21 or deleted²², making it a good candidate gene for this syndrome. The deletion varies widely in size, from 130kb to 9Mb. ^22,23,24 Recent findings therefore recommend the use of 22q subtelomeric probes distal to the ARSA gene for examining all 22q13.3 deletions. ^24,25

Reference:/Bibliographie/Literatur/Bibliografia

1. Pinsky L. and DiGeorge, A.M. (1965) J Pediatr 66: 1049-54
2. Shprintzen, R.J. et al (1978) Cleft Palate J 15: 56-62
3. Burn, J. et al (1993) J Med Genet 30: 822-824
4. Wilson, D.I. et al (1993) J Med Genet 30: 852-856
5. Driscoll, D.A. et al (1992) J Am Hum Genet 50: 924-933
6. Burn, J. (1993) ibid., p.822
7. Goldmuntz, E. et al (1993) J Med Genet 30: 807-812
8. Devriendt, K. et al (1998) J Med Genet 35: 789-790
9. Driscoll, D.A. et al (1990) Am J Med Genet . Suppl 47: A215
10. Scambler, P.J. et al (1991) Genomics 10: 201-206
11. Halford, S. et al (1993) Hum Mol Genet 2 (12): 2099-2107
12. Carlson, C. et al (1997) Am J Hum Genet 61: 620-629
13. Jerome, L.A. and Papaioannou V.E. (2001) Nature Genet 27: 286-291
14. Lidsay, E.A. et al (2001) Nature 409: 379-383
15. Arnold, J.S. et al (2006) Hum Mol Genet 15:1629-1639
16. Paylor et al (2006) PNAS USA 103:7729-7734
17. Phelan, M.C. et al (2001) Am J Med Genet 101(2): 91-99
18. Prasad, C. et al (2000) Clin Genet 57(2): 103-109
19. Beeckers T.M. et al (2002) J Neurochem 81(5): 903-910
20. Bonaglia M.C. et al (2001) Am J Hum Genet 69(2): 261-268
21. Anderlid BM. et al (2002) Hum Genet 110(5): 439-443
22. Wilson H.L. et al (2003) J Med Genet 40(8): 575-584
23. Dupont C. et al (2003) French Speaking Cytogeneticists Association Congress
24. Luciani J. et al (2003) J Med Genet 40(9): 690-696
25. Chen C.P. et al (2003) Prenat Diagn 23(6): 504-508