AbstractBeckwith-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. However, this is not without its limitations, especially in the detection of low-level mosaicism.
In order to evaluate the relationship between the clinical presentation of suspected BWS and IC1/2 methylation abnormalities we reviewed the results of over 1,000 referrals for molecular diagnostic testing.507/1,091 (46.5%) referrals 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. We found significant associations of macroglossia and facial naevus flammeus with IC2 epimutations (P < 0.01), and organomegaly with paternal uniparental disomy and IC1 (P < 0.001).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 - 0.87) compared to previous criteria. Indeed, we found that macroglossia and exomphalos are most predictive of an abnormal BWS methylation profile.
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.
|Date of Award||2016|
|Sponsors||Action Medical Research|
|Supervisor||Jonathan Berg (Supervisor)|