title: Methylation analysis and diagnostics of Beckwith-Wiedemann syndrome in 1,000 subjects.
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.
authors: 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.
authors: Abdulla
authors: A
authors: Ibrahim
authors: 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.
authors: Gail
authors: G
authors: Kirby
authors: West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
authors: Carol
authors: C
authors: Hardy
authors: 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.
authors: Renuka P
authors: RP
authors: Dias
authors: 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.
authors: Louise
authors: L
authors: Tee
authors: 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.
authors: Derek
authors: D
authors: Lim
authors: Department of Clinical Genetics, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors: Jonathan
authors: J
authors: Berg
authors: West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham B15 2TG, UK.
authors: Fiona
authors: F
authors: MacDonald
authors: Wellcome Trust Clinical Research Facility, University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham B15 2TH, UK.
authors: Peter
authors: P
authors: Nightingale
authors: 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.
authors: Eamonn R
authors: ER
authors: Maher
keywords: 11p15; Beckwith-Wiedemann syndrome; Diagnostic criteria; Imprinting; Scoring system