DiGeorge / VCFS TUPLE 1 / 22q Deletion Syndrome LPU004 - 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 1:5000 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 Citrate Transport Protein (CTP) and the Clathrin heavy chain genes (CLTD) ¹² which may be implicated in the aetiology of VCFS.

The DiGeorge/VCFS Region probe is approximately 120 Kb encompassing the entire TUPLE1 gene and flanking DNA. It is intended to identify 22q11.2 deletions of DiGeorge and associated syndromes. It is designed for fluorescence in situ hybridisation of interphase cells and metaphase chromosomes from fixed cultured peripheral blood cells. The 22qter subtelomere specific probe (clone N85A3) allows identification of chromosome 22 and acts as a control probe.

Note: 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. ¹⁵ Some deletions of the terminal region of chromosome 22q are cytogenetically visible. However, a few cases of cryptic deletions have been reported, ^15,16 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 ²² gene, coding for a structural protein of the postsynaptic density of excitation synapses and expressed in the cortex and cerebellum of the brain¹⁷, was disrupted ^17,18,19 or deleted²⁰, making it a good candidate gene for this syndrome. The deletion varies widely in size, from 130kb to 9Mb. ^20,21,22 Recent findings therefore recommend the use of 22q subtelomeric probes distal to the ARSA gene for examining all 22q13.3 deletions. ^22,23

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. Tezenas Du Montcel, S. et al (1996) J Med Genet 33: 719
9. Driscoll, D.A. et al (1990) Am J Med Genet . Suppl 37: 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. Goldmuntz E. et al (1996) Genomics 33: 271-276
14. pers. comm. P.Scambler, Instit. Child Health, Guy's Tower, London
15. Phelan, M.C. et al (2001) Am J Med Genet 101(2): 91-99
16. Prasad, C. et al (2000) Clin Genet 57(2): 103-109
17. Beeckers T.M. et al (2002) J Neurochem 81(5): 903-910
18. Bonaglia M.C. et al (2001) Am J Hum Genet 69(2): 261-268
19. Anderlid BM. et al (2002) Hum Genet 110(5): 439-443
20. Wilson H.L. et al (2003) J Med Genet 40(8): 575-584
21. Dupont C. et al (2003) French Speaking Cytogeneticists Association Congress
22. Luciani J. et al (2003) J Med Genet 40(9): 690-696
23. Chen C.P. et al (2003) Prenat Diagn 23(6): 504-508