Journal of Genetic Counseling

, Volume 22, Issue 1, pp 22–26 | Cite as

Unintended Diagnosis of Von Hippel Lindau Syndrome Using Array Comparative Genomic Hybridization (CGH): Counseling Challenges Arising from Unexpected Information

Case Presentation

Abstract

Array Comparative Genomic Hybridization (array CGH) is a powerful tool for identifying genomic imbalances and providing a diagnosis in individuals with a normal karyotype. It has been particularly useful in the investigation of individuals with developmental delay +/−, dysmorphic features and/or multiple congenital abnormalities. However, this non-targeted method of scanning the whole genome can reveal unexpected information. We present a case where array CGH identified the cause of a proband’s moderate mental retardation by discovery of a de novo deletion of chromosome 3p25.3. This deletion was shown to contain at least 25 genes including the VHL gene, the deletion or mutation of which leads to Von Hippel Lindau (VHL) syndrome. Presymptomatic testing for VHL is usually offered after appropriate genetic counseling about the implications of this condition. Therefore, scanning the genome by array CGH presents a number of challenges for the genetic counselor. We suggest that further understanding of the psychosocial effects of array CGH is needed in order for appropriate pre- and post-test counseling to be provided.

Keywords

Array Comparative Genomic Hybridization Array CGH Von Hippel Lindau Syndrome Unexpected diagnosis Chromosomal abnormality 

References

  1. Charlesworth, M., Verbeke, C. S., Falk, G. A., Walsh, M., Smith, A. M., & Morris-Stiff, G. (2012). Pancreatic lesions in von Hippel-Lindau disease? A systematic review and meta-synthesis of the literature. Journal of Gastrointestinal Surgery, 16(7), 1422–1428.Google Scholar
  2. Cottrell, C. E., Prior, T. W., Pyatt, R., Astbusy, C., Reshmi, S., Bartholomew, D., et al. (2010). Unexpected detection of dystrophin gene deletions by array comparative genomic hybridization. American Journal of Medical Genetics. Part A, 152A(9), 2301–2307.PubMedCrossRefGoogle Scholar
  3. Darilek, S., Ward, P., Pursley, A., Plunkett, K., Furman, P., Magoulas, P., et al. (2008). Pre- and postnatal genetic testing by array-comparative genomic hybridisation: genetic counseling perspectives. Genetics in Medicine, 10(1), 13–18.PubMedCrossRefGoogle Scholar
  4. Fraser, L., Watts, S., Cargill, A., Sutton, S., & Hodgson, S. (2007). Study comparing two types of screening provision for people with von Hippel-Lindau disease. Familial Cancer, 6, 103–111.PubMedCrossRefGoogle Scholar
  5. Fruhman, G., & Van den Veyver, I. B. (2010). Applications of Array Comparative Genomic Hybridization in Obstetrics. Obstetrics and Gynaecology Clinics of North America, 37(1), 71–85.CrossRefGoogle Scholar
  6. Glasker, S. (2005). Central nervous system manifestations in VHL: genetics, pathology and clinical phenotypic features. Familial Cancer, 4, 37–42.PubMedCrossRefGoogle Scholar
  7. Heald, B., Moran, R., Milas, M., Burke, C., & Eng, C. (2007). Familial adenomatous polyposis in a patient with unexplained mental retardation. Nature Clinical Practice Neurology, 3(12), 694–700.PubMedCrossRefGoogle Scholar
  8. Kim, H. J., Butman, J. A., Brewer, C., Zalewski, C., Vortmeyer, A. O., Glenn, G., et al. (2005). Tumors of the endolymphatic sac in patients with von Hippel-Lindau disease: implications for their natural history, diagnosis, and treatment. Journal of Neurosurgery, 102(3), 503–512.PubMedCrossRefGoogle Scholar
  9. Kim, J. J., Rini, B. I., & Hansel, D. E. (2010). Von Hippel Lindau Syndrome. Advances in Experimental Medicine and Biology, 68, 228–249.CrossRefGoogle Scholar
  10. Klungland, A., Rosewell, I., Hollenbach, S., Larsen, E., Daly, G., Epe, B., et al. (1999). Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proceedings of the National Academy of Sciences of the United States of America, 96(23), 13300–13305.PubMedCrossRefGoogle Scholar
  11. Kreusel, K. M., Bechrakis, N. E., Krause, L., Neumann, H. P. H., & Foerster, M. H. (2006). Retinal Angiomatosis in von Hippel-Lindau Disease – a longitudinal opthalmologic study. Opthalmology, 113(8), 1418–1424.CrossRefGoogle Scholar
  12. Lewis, C., Skirton, H., & Jones, R. (2010). Living without a diagnosis: the parental experience. Genetic Testing and Molecular Biomarkers, 14(6), 1–9.CrossRefGoogle Scholar
  13. Lonser, R. R., Glenn, G. M., Walther, M., Chew, E. Y., Libutti, S. K., Linehan, W. M., et al. (2003). Von Hippel-Lindau disease. The Lancet, 361, 2059–2067.CrossRefGoogle Scholar
  14. Lu, X., Shaw, C. A., Patel, A., Li, J., Cooper, M. L., Wells, W. R., et al. (2007). Clinical Implementation of chromosomal microarray analysis: summary of 2513. Postnatal Cases, PloS One, 2(3), e327.Google Scholar
  15. Mathew, C. G. (2006). Fanconi anaemia genes and susceptibility to cancer. Oncogene, 25, 5875–5884.PubMedCrossRefGoogle Scholar
  16. Netzer, C., Klein, C., Kohlase, J., & Kubisch, C. (2009). New challenges for informed consent through whole genome array testing. Journal of Medical Genetics, 46, 495–496.PubMedCrossRefGoogle Scholar
  17. Peshkin, B. N., DeMarco, T. A., Garber, J. E., Valdimarsdottir, H. B., Patenaude, A. F., Schneider, K. A., et al. (2009). Brief Assessment of Parent’s Attitudes Toward Testing Minor Children for Hereditary Breast/Ovarian Cancer Genes: Development and Validation of the Pediatric BRCA1/2 Testing Attitudes Scale (P-TAS). Journal of Pediatric Psychology, 34(6), 627–638.PubMedCrossRefGoogle Scholar
  18. Pichert, G., Mohammed, S. N., Ahn, J. W., Ogilvie, C. M., & Izatt, L. (2011). Unexpected findings in cancer predisposition genes detected by array comparative genomic hybridisation: what are the issues? Journal of Medical Genetics, 48(8), 535–539.Google Scholar
  19. Pohjola, P., de Leeuw, N., Penttinen, M., Kaariainen, H., (2009). Terminal 3p deletions in two families – correlation between molecular karyotype and phenotype. American Journal of Medical Genetics – Part A, 152A, 441–446.Google Scholar
  20. Priesemann, M., Davies, K. M., Perry, L. A., Drake, W. M., Chew, S. L., Monson, J. P., et al. (2006). Benefits of screening in von Hippel-Lindau disease-comparison of morbidity associated with initial tumours in affected parents and children. Hormone Research in Pædiatrics, 66, 1–5.Google Scholar
  21. Rasmussen, A., Alonso, E., Ochoa, A., De Biase, I., Familiar, I., Yescas, P., et al. (2010). Uptake of genetic testing and long term tumor surveillance in von Hippel Lindau disease. BMC Medical Genetics, 11, 4–12.PubMedCrossRefGoogle Scholar
  22. Schultz, J. M., Yang, Y., Caride, A. J., Filoteo, A. G., Penheiter, A. R., Lagziel, A., et al. (2005). Modification of Human Hearing Loss by Plasma Membrane Calcium Pump PMCA2. The New England Journal of Medicine, 352, 1557–1564.PubMedCrossRefGoogle Scholar
  23. Schwarzbraun, T., Obenauf, A. C., Langmann, A., Gruber-Sedlmayr, U., Wagner, K., Speicher, M. R., et al. (2009). Predictive, Diagnosis of the cancer prone Li-Fraumeni syndrome by accident: new challenges through whole genome array testing. Journal of Medical Genetics, 46, 341–344.PubMedCrossRefGoogle Scholar
  24. Sessa, A., Battini, G., Meroni, M., Pitingolo, F., Righetti, M., Ciotti, P., et al. (2005). Multifocal Bilateral renal cell carcinoma and retinal angiomas in a patient with de novo von Hippel-Lindau disease: identification of a new germline mutation. Journal of Nephrology, 18(2), 209–212.PubMedGoogle Scholar
  25. Shinawi, M., & Cheung, S. W. (2008). The array CGH and its clinical applications. Drug Discovery Today, 13(17–18), 760–770.PubMedCrossRefGoogle Scholar
  26. Shuib, S., McMullan, D., Rattenberry, E., Barber, R. M., Rahman, F., Zatyka, M., et al. (2009). Microarray Based Analysis of 3p25-p26 Deletions (3p- Syndrome). American Journal of Medical Genetics. Part A, 149A, 2099–2105.PubMedCrossRefGoogle Scholar
  27. Vermeer, S., Koolen, D. A., Visser, G., Brackel, H. J., van der Burgt, I., de Leeuw, N., et al. (2007). A Novel microdeletion in 1(p34.2p34.3), involving the SLC2A1 (GLUT1) gene, and severe delayed development. Developmental Medicine and Child Neurology, 49(5), 380–384.Google Scholar
  28. Zatyka, M., Priestley, M., Ladusans, E. J., Fryer, A. E., Mason, J., Latif, F., et al. (2005). Analysis of CRELD1 as a candidate 3p25 atrioventricular septal defect locus (AVSD2). Clinical Genetics, 67(6), 526–528.PubMedCrossRefGoogle Scholar

Copyright information

© National Society of Genetic Counselors, Inc. 2012

Authors and Affiliations

  • Jennifer Hogan
    • 1
    • 4
  • A. Turner
    • 1
    • 2
  • K. Tucker
    • 1
    • 3
  • L. Warwick
    • 1
  1. 1.ACT Genetic Service The Canberra HospitalCanberraAustralia
  2. 2.Department of Medical GeneticsSydney Children’s HospitalSydneyAustralia
  3. 3.Hereditary Cancer ClinicPrince of Wales HospitalSydneyAustralia
  4. 4.ACT Genetics ServiceWodenAustralia

Personalised recommendations