Skip to main content
SpringerLink
Log in

Molecular and Genetic Aspects of DiGeorge/Velocardiofacial Syndrome

  • Protocol
Book cover Congenital Heart Disease

Part of the book series: Methods in Molecular Medicine ((MIMM,volume 126))

Abstract

Cytogenetic, molecular, and clinical genetic studies have contributed to our understanding of the etiology, pathogenesis, and natural history of DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). Submicroscopic deletions of chromosome 22q11.2 are the leading cause of both of these disorders. The 22q11.2 deletion syndrome is recognized as one of the most common microdeletion syndromes. The clinical features are highly variable and include a variety of congenital anomalies, medical problems, and cognitive and neuropsychological difficulties.

Infrequently, other chromosomal rearrangements are found in patients with DGS/VCFS, and, rarely, point mutations in the gene TBX1, a transcription factor, that maps to the deleted region. The most sensitive and widely used diagnostic test for detecting the 22q11.2 deletion is fluorescence in situ hybridization using probes from the commonly deleted region. Alternatively, polymerase chain reaction can be performed to confirm failure to inherit a parental allele in the region or to determine copy number. Prenatal diagnosis is also available, particularly when a conotruncal cardiac defect is identified during a pregnancy or when a parent carries a deletion. Genetic counseling is recommended before testing to review the natural history of the disorder, testing options, and test sensitivity and limitations.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. DiGeorge, A. M. (1965) Discussion on a new concept of the cellular basis of immunology. J. Pediatr. 67, 907.

    Article  Google Scholar 

  2. Conley, M. E., Beckwith, J. B., Mancer, J. F. K., and Tenckhoff, L. (1979) The spectrum of the DiGeorge syndrome. J. Pediatr. 94, 883–890.

    Article  CAS  PubMed  Google Scholar 

  3. Lammer, E. J. and Opitz, J. M. (1986) The DiGeorge anomaly as a developmental field defect. Am. J. Med. Genet. 29, 113–127.

    Article  Google Scholar 

  4. Scambler, P. J., Carey, A. H., Wyse, R. K. H., et al. (1991) Microdeletions within 22q11 associated with sporadic and familial DiGeorge syndrome. Genomics 20, 201–206.

    Article  Google Scholar 

  5. Driscoll, D. A., Budarf, M. L., and Emanuel, B. S. (1992a) A genetic etiology for DiGeorge syndrome: consistent deletions and microdeletions of 22q11. Am. J. Hum. Genet. 50, 924–933.

    CAS  PubMed  Google Scholar 

  6. Driscoll, D. A., Spinner, N. B., Budarf, M. L., et al. (1992b) Deletions and microdeletions of 22q11.2 in velo-cardio-facial syndrome. Am. J. Med. Genet. 44, 261–268.

    Article  CAS  PubMed  Google Scholar 

  7. Burn, J., Takao, A., Wilson, D., et al. (1993) Conotruncal anomaly face syndrome is associated with a deletion within chromosome 22. J. Med. Genet. 30, 822–824.

    Article  CAS  PubMed  Google Scholar 

  8. Goldmuntz, E., Driscoll, D., Budarf, M. L., et al. (1993) Microdeletions of chromosomal region 22q11 in patients with congenital conotruncal cardiac defects. J. Med. Genet. 30, 807–812.

    Article  CAS  PubMed  Google Scholar 

  9. Ryan, A. K., Goodship, J. A., Wilson, D. I., et al. (1997) Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J. Med. Genet. 34(10), 798–804.

    Article  CAS  PubMed  Google Scholar 

  10. McDonald-McGinn, D. M., Kirschner, R., Goldmuntz, E., et al. (1999) The Philadelphia Story: The 22q11.2 Deletion: Report on 250 Patients. Genetic. Counseling 10(1), 11–24.

    CAS  PubMed  Google Scholar 

  11. Swillen, A., Vogels, A., Devriendt, K., Fryns, J. P. (2000) Chromosome 22q11 deletion syndrome: Update and review of the clinical features, cognitive-behavioral spectrum, and psychiatric complications. Am. J. Med. Genet. 97, 128–135.

    Article  CAS  PubMed  Google Scholar 

  12. Moss, E., Batshaw, M. L., Solot, C. B., et al. (1999) Psychoeducational profile of the 22q11.2 microdeletion: a comples pattern. J. Pediatr. 134, 193–198.

    Article  CAS  PubMed  Google Scholar 

  13. Woodin, M., Wang, P. P., Aleman, D., McDonald-McGinn, D., Zackai, E., Moss, E. (2001) Neuropsychological profile of children and adolescents with the 22q11.2 microdeletion. Genet. Med. 3, 34–44.

    Article  CAS  PubMed  Google Scholar 

  14. Matsuoka, R., Takao, A., Kimura, M., et al. (1994) Confirmation that the conotruncal anomaly face syndrome is associated with a deletion within 22q11.2. Am. J. Med. Genet. 53, 285–289.

    Article  CAS  PubMed  Google Scholar 

  15. McDonald-McGinn, D. M., Driscoll, D. A., Bason, L., et al. (1995) Autosomal dominant “Optiz” GBBB syndrome due to a 22q11.2 deletion. Am. J. Med. Genet. 59, 103–113.

    Article  CAS  PubMed  Google Scholar 

  16. Giannotti, A., Digilio, M. C., Marino, B., Mingarelli, R., and Dallapiccola, B. (1994) Cayler cardiofacial syndrome and del 22q11: Part of the CATCH22 phenotype. Am. J. Med. Genet. 53, 303–304.

    Article  CAS  PubMed  Google Scholar 

  17. Driscoll, D. A., Salvin, J., Sellinger, B., et al. (1993): Prevalence of 22q11 microdeletions in DiGeorge and velocardiofacial syndromes: implications for genetic counselling and prenatal diagnosis. J. Med. Genet. 30:813–817.

    Article  CAS  PubMed  Google Scholar 

  18. Lindsay, E. A., Greenberg, F., Shaffer, L. G,. Shapira, S. K., Scambler, P. J., and Baldini, A. (1995) Submicroscopic deletions at 22q11.2: variability of the clinical picture and delineation of a commonly deleted region. Am. J. Med. Genet. 56, 191–197.

    Article  CAS  PubMed  Google Scholar 

  19. Devriendt, K., Fryns, J.-P., Van Thienen, M.-N., and Keymolen, K. (1998) The annual incidence of DiGeorge/velocardiofacial syndrome. J. Med. Genet. 35, 789–790.

    Article  CAS  PubMed  Google Scholar 

  20. Botto, L. D., May, K., Fernhoff, P. M., et al. (2003) A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112, 101–107.

    Article  PubMed  Google Scholar 

  21. Kelley, R. I., Zackai, E. H., Emanuel, B. S., Kistenmacher, M., Greenberg, F., and Punnett, H. H. (1982) The association of the DiGeorge anomalad with partial monosomy of chromosome 22. J. Pediatr. 101:197–200.

    Article  CAS  PubMed  Google Scholar 

  22. Greenberg, F. (1993) DiGeorge syndrome: an historical review of clinical and cytogenetic features. J. Med. Genet. 30, 803–806.

    Article  CAS  PubMed  Google Scholar 

  23. Goldmuntz, E., Clark, B. J., Mitchell, L. E., et al. (1998) Frequency of 22q11 deletions in patients with conotruncal defects. J. Am. Coll. Cardiol. 32, 492–298.

    Article  CAS  PubMed  Google Scholar 

  24. Fokstuen, S., Arbenz, U., Artan, S., et al. (1998) 22q11.2 deletions in a series of patients with non-selective congenital heart defects: incidence, type of defects and parental origin. Clin. Genet. 53, 64–69.

    Article  Google Scholar 

  25. Voigt, R., Maier-Weidmann, M., Lange, P. E., and Haaf, T. (2002) Chromosome 10p13-14 and 22q11 deletion screening in 100 patients with isolated and syndromic conotruncal heart defects. J. Med. Genet. 39, e16.

    Article  CAS  PubMed  Google Scholar 

  26. Lewin, M. B., Lindsay, E. A., Jurecic, V., Goytia, V., Towbin, J. A., and Baldini, A. (1997) A genetic etiology for interruption of the aortic arch type B. Am. J. Cardiol. 80, 493–497.

    Article  CAS  PubMed  Google Scholar 

  27. Rauch, A., Hofbeck, M., Leipold, G., et al. (1998) Incidence and significance of 22q11.2 hemizygosity in patients with interrupted aortic arch. Am. J. Med. Genet. 78, 322–331.

    Article  CAS  PubMed  Google Scholar 

  28. Momma, K., Ando, M., Matsuoka, R. (1997) Truncus arteriosus communis associated with chromosome 22q11 deletion. J. Am. Coll. Cardiol. 30, 1067–1071.

    Article  CAS  PubMed  Google Scholar 

  29. McElhinney, D. B., Driscoll, D. A., Emanuel, B. S., and Goldmuntz, E. (2003) Chromosome 22q11 deletion in patients with truncus arteriosus. Pediatr. Cardiol. 24, 569–573.

    Article  CAS  PubMed  Google Scholar 

  30. McElhinney, D. B., Driscoll, D. A., Levin, E., Jawad, A. F., Emanuel, B. S., and Goldmuntz, E. (2003) Chromosome 22q11 deletion in patients with ventricular septal defect: frequency and associated cardiovascular anomalies. Pediatrics 112(6 Pt 1), e472–e476.

    Article  PubMed  Google Scholar 

  31. Lu, J.-H., Chung, M.-Y., Hwang, B., and Chien, H.-P. (1999) Prevalence and parental origin in Tetralogy of Fallot associated with chromosome 22q11 microdeletion. Pediatrics 104, 87–90.

    Article  CAS  PubMed  Google Scholar 

  32. Derbent, M., Yilmaz, Z., Baltaci, V., Saygih, A., Varan, B., and Tokel, K. (2003) Chromosome 22q11.2 deletion and phenotypic features in 30 patients with conotruncal heart defects. Am. J. Med. Genet. 116A, 129–135.

    Article  PubMed  Google Scholar 

  33. Digilio, M.C., Marino, B., Giannotti, A., Mingarelli, R., and Dallapiccola, B. (1999) Guidelines for 22q11 deletion screening of patients with conotruncal defects. J. Am. Col. Cardiol. 33, 1746–1747.

    Article  CAS  Google Scholar 

  34. Goldmuntz, E., Clark, B. J., Mitchell, L. E., et al. (1999) Guidelines for 22q11.2 deletion screening of patients with conotruncal defects. J. Am. Col. Cardiol. Letter to the Editor. Reply. 33, 1747–1748.

    Article  Google Scholar 

  35. Gerdes, M., Solot, S., Wang, P. P., McDonald-McGinn, D. M., and Zackai, E. Z. (2001) Taking advantage of early diagnosis: preschool children with the 22q11.2 deletion. Genet. Med. 3, 40–44.

    Article  CAS  PubMed  Google Scholar 

  36. Driscoll, D. A. (2001) Prenatal diagnosis of the 22q11.2 deletion syndrome. Genet. Med. 3, 14–18.

    Article  CAS  PubMed  Google Scholar 

  37. Manji, S., Roberson, J. R., Wiktor, A., et al. (2001) Prenatal diagnosis of 22q11.2 deletion when ultrasound examination reveals a heart defects. Genet. Med. 3, 65–66.

    Article  CAS  PubMed  Google Scholar 

  38. Iwarsson, E., Ahrlund-Richter, L., Inzunza, J., et al. (1998) Preimplantation genetic diagnosis of DiGeorge syndrome. Molec. Hum. Reprod. 4, 871–875.

    Article  CAS  PubMed  Google Scholar 

  39. Hatchwell, E., Long, F., Wilde, J., Crolla, J., and Temple, K. (1998) Molecular confirmation of germ line mosaicism for a submicroscopic deletion of chromosome 22q11. Am. J. Med. Genet. 78, 103–106.

    Article  CAS  PubMed  Google Scholar 

  40. Sandrin-Gardia, P., Macedo, C., Martelli, L. R., et al. (2002) Short report: recurrent 22q11.2 deletion in a sibship suggestive of parental germline mosaicism in velocardiofacial syndrome. Clin. Genet. 61, 380–383.

    Article  Google Scholar 

  41. Desmaze, C., Scambler, P., Prieur, M., et al. (1993) Routine diagnosis of DiGeorge syndrome by fluorescent in situ hybridization. Hum. Genet. 90, 663–665.

    Article  CAS  PubMed  Google Scholar 

  42. Wilson, D. I., Cross, I. E., Goodship, J. A., et al. (1992) A prospective cytogenetic study of 36 cases of DiGeorge syndrome. Am. J. Hum. Genet. 51, 957–963.

    CAS  PubMed  Google Scholar 

  43. Berend, S. A., Spikes, A. S., Kashork, C. D., et al. (2000) Dual-probe fluorescence in situ hybridization assay for detecting deletions associated with VCFS/ DiGeorge syndrome I and DiGeorge syndrome II loci. Am. J. Med. Genet. 91, 313–317.

    Article  CAS  PubMed  Google Scholar 

  44. Shaikh, T. S., Kurahashi, H., Saitta, S. C., et al. (2000) Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis. Hum. Molec. Genet. 9, 489–501.

    Article  CAS  PubMed  Google Scholar 

  45. Saitta, S. C., Harris, S. E., Gaeth, A. P., et al. (2004) Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum. Mol. Genet. 13, 417–428.

    Article  CAS  PubMed  Google Scholar 

  46. Rauch, A., Pfeiffer, R. A., Leipold, G., Singer, H., Tigges, M., and Hofbeck, M. (1999) A novel 22q11.2 microdeletion in DiGeorge syndrome. Am. J. Hum. Genet. 64, 659–666.

    Article  CAS  PubMed  Google Scholar 

  47. Saitta, S. C., McGrath, J. M., Mensch, H., Shaikh, T. H., Zackai, E. H., and Emanuel, B. S. (1999) A 22q11.2 deletion that excludes UFD1L and CDC45L in a patient with conotruncal and craniofacial defects. Am. J. Hum. Genet. 65, 562–566.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  49. Lindsay, E. A., Vitelli, F., Su, H., et al. (2002) tbx 1 haploinsufficiency in the DiGeorge syndrome region causes aortic arch defects in mice. Nature 410, 97–101.

    Article  Google Scholar 

  50. Jerome, L. A. and Papaioannou, V. E. (2001) DiGeorge syndrome phenotype in mice mutant for the T-box gene, TBX1. Nat. Genet. 27, 286–291.

    Article  CAS  PubMed  Google Scholar 

  51. Gong, W., Gottlieb, S., Collins, J., et al. (2001) Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects. J. Med. Genet. 38, E45.

    Article  CAS  PubMed  Google Scholar 

  52. Conti, E., Grifone, N., Sarkozy, A., et al. (2003) DiGeorge subtypes of nonsyndromic conotruncal defects: evidence against a major role of TBX1 gene. Eur. J. Hum. Genet. 11, 349–351.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  54. Driscoll, D. A., Emanuel, B. S., Mitchell, L. E., and Budarf, M. L. (1997) PCR assay for screening patients at risk for 22q11.2 deletion. Genet. Test. 1, 109–113.

    Article  CAS  PubMed  Google Scholar 

  55. Bonnet, D., Cormier-Daire, V., Kachaner, J., et al. (1997) Microsatellite DNA markers detects 95% of chromosome 22q11 deletions. Am. J. Med. Genet. 68, 182–184.

    Article  CAS  PubMed  Google Scholar 

  56. Saitta, S. C., Harris, S. E., McDonald-McGinn, D. M., et al. (2004) Independent de novo 22q11.2 deletions in first cousins with DiGeorge/velocardiofacial syndrome. Am. J. Med. Genet. 124A, 313–317.

    Article  PubMed  Google Scholar 

  57. Kariyazono, J., Ohno, T., Ihara, K., et al. (2001) Rapid detection of the 22q11.2 deletion with quantitative real-time PCR. Molec. Cell. Probes 25, 71–73.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Reproductive Genetics, Department of Obstetrics and Gynecology, University of Pennsylvania Medical Center, Philadelphia, PA

    Deborah A. Driscoll

Authors
  1. Deborah A. Driscoll
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Transplantation Biology Research Lab Division of Cardiothoracic Surgery Children’s Hospital of Los Angeles, Los Angeles, CA, USA

    Mary Kearns-Jonker

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc.

About this protocol

Cite this protocol

Driscoll, D.A. (2006). Molecular and Genetic Aspects of DiGeorge/Velocardiofacial Syndrome. In: Kearns-Jonker, M. (eds) Congenital Heart Disease. Methods in Molecular Medicine, vol 126. Humana Press. https://doi.org/10.1385/1-59745-088-X:43

Download citation

  • DOI: https://doi.org/10.1385/1-59745-088-X:43

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-375-6

  • Online ISBN: 978-1-59745-088-1

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation