Display options
Cite
Ibrahim A, Kirby G, Hardy C, et al. Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects. Clin Epigenetics. 2014;6(1):11doi: 10.1186/1868-7083-6-11.
Ibrahim, A., Kirby, G., Hardy, C., Dias, R. P., Tee, L., Lim, D., Berg, J., MacDonald, F., Nightingale, P., & Maher, E. R. (2014). Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects. Clinical epigenetics, 6(1), 11. https://doi.org/10.1186/1868-7083-6-11
Ibrahim, Abdulla, et al. "Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects." Clinical epigenetics vol. 6,1 (2014): 11. doi: https://doi.org/10.1186/1868-7083-6-11
Ibrahim A, Kirby G, Hardy C, Dias RP, Tee L, Lim D, Berg J, MacDonald F, Nightingale P, Maher ER. Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects. Clin Epigenetics. 2014 Jun 04;6(1):11. doi: 10.1186/1868-7083-6-11. eCollection 2014. PMID: 24982696; PMCID: PMC4064264.
Copy Download .nbib Format: NLM
Share it on

Clin Epigenetics. 2014 Jun 04;6(1):11. doi: 10.1186/1868-7083-6-11. eCollection 2014.

Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects.

Clinical epigenetics

Abdulla Ibrahim, Gail Kirby, Carol Hardy, Renuka P Dias, Louise Tee, Derek Lim, Jonathan Berg, Fiona MacDonald, Peter Nightingale, Eamonn R Maher

Affiliations

  1. Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK ; Department of Clinical Genetics, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
  2. Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
  3. West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
  4. Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK ; West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
  5. Department of Clinical Genetics, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
  6. Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham B15 2TH, UK.
  7. Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0QQ, UK ; Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.

PMID: 24982696 PMCID: PMC4064264 DOI: 10.1186/1868-7083-6-11

Abstract

BACKGROUND: Beckwith-Wiedemann syndrome (BWS), a congenital overgrowth disorder with variable expressivity and a predisposition to tumorigenesis, results from disordered expression and/or function of imprinted genes at chromosome 11p15.5. There are no generally agreed clinical diagnostic criteria, with molecular studies commonly performed to confirm diagnosis. In particular, methylation status analysis at two 11p15.5 imprinting control centres (IC1 and IC2) detects up to 80% of BWS cases (though low-level mosaicism may not be detected). In order to evaluate the relationship between the clinical presentation of suspected BWS and IC1/2 methylation abnormalities we reviewed the results of >1,000 referrals for molecular diagnostic testing.

RESULTS: Out of 1,091 referrals, 507 (46.5%) had a positive diagnostic test for BWS. The frequency of tumours was 3.4% in those with a molecular diagnosis of BWS. Previously reported genotype-phenotype associations with paternal uniparental disomy, IC1, and IC2 epimutation groups were confirmed and potential novel associations detected. Predictive values of previously described clinical diagnostic criteria were compared and, although there were differences in their sensitivity and specificity, receiver operating characteristic (ROC) analysis demonstrated that these were not optimal in predicting 11p15.5 methylation abnormalities. Using logistic regression, we identified clinical features with the best predictive value for a positive methylation abnormality. Furthermore, we developed a weighted scoring system (sensitivity 75.9%, and specificity 81.8%) to prioritise patients presenting with the most common features of BWS, and ROC analysis demonstrated superior performance (area under the curve 0.85, 95% CI 0.83 to 0.87) compared to previous criteria.

CONCLUSIONS: We suggest that this novel tool will facilitate selection of patients with suspected BWS for routine diagnostic testing and so improve the diagnosis of the disorder.

Keywords: 11p15; Beckwith-Wiedemann syndrome; Diagnostic criteria; Imprinting; Scoring system

References

  1. Horm Res Paediatr. 2013;80(6):457-65 - PubMed
  2. Am J Med Genet A. 2009 Aug;149A(8):1691-7 - PubMed
  3. Genomics. 2007 May;89(5):613-7 - PubMed
  4. J Pediatr. 1998 Mar;132(3 Pt 1):398-400 - PubMed
  5. J Med Genet. 2000 Dec;37(12):921-6 - PubMed
  6. Am J Med Genet C Semin Med Genet. 2013 May;163C(2):131-40 - PubMed
  7. Nat Genet. 1996 Oct;14(2):171-3 - PubMed
  8. Eur J Hum Genet. 2005 Sep;13(9):1025-32 - PubMed
  9. Nat Rev Genet. 2001 Jan;2(1):21-32 - PubMed
  10. J Med Genet. 1999 Jul;36(7):518-23 - PubMed
  11. Curr Opin Endocrinol Diabetes Obes. 2014 Feb;21(1):30-8 - PubMed
  12. Am J Med Genet A. 2013 May;161A(5):993-1001 - PubMed
  13. Proc Natl Acad Sci U S A. 1999 Jul 6;96(14):8064-9 - PubMed
  14. Clin Genet. 1994 Aug;46(2):168-74 - PubMed
  15. Chest. 2007 Feb;131(2):383-8 - PubMed
  16. Hum Mol Genet. 2001 Dec 15;10(26):2989-3000 - PubMed
  17. Epigenomics. 2009 Dec;1(2):347-69 - PubMed
  18. Eur J Hum Genet. 2014 Mar;22(3): - PubMed
  19. Eur J Hum Genet. 2001 Jun;9(6):409-18 - PubMed
  20. Genet Med. 2009 Mar;11(3):220-2 - PubMed
  21. J Med Genet. 2003 Nov;40(11):797-801 - PubMed
  22. J Pediatr. 2004 Dec;145(6):796-9 - PubMed
  23. Hum Reprod. 2009 Mar;24(3):741-7 - PubMed
  24. Ann Thorac Surg. 2004 Apr;77(4):1142-4 - PubMed
  25. J Med Genet. 2008 Feb;45(2):106-13 - PubMed
  26. Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5203-8 - PubMed
  27. J Genet Hum. 1964 Sep;13:223-32 - PubMed
  28. Mol Aspects Med. 2013 Jul-Aug;34(4):826-40 - PubMed
  29. Eur J Hum Genet. 2010 Jan;18(1):8-14 - PubMed

Publication Types