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

Abstract

BackgroundBeckwith-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.ResultsOut 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.ConclusionsWe 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.

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

“…4,[9][10][11]13,[27][28][29] In this study we further investigated these correlations providing data on a large cohort of fully characterized BWS patients with 11p15 region molecular defects. Our analysis evidences in the four BWS molecular subtypes differences in the incidence of many phenotypic traits, such as growth pattern, prevalence and severity of abdominal wall defects, macrosomia, nevus flammeus, ear signs, renal malformations, ureteral anomalies, organ enlargement, polyhydramnios, cancer incidence, and histotypes.…”

“…4,[9][10][11]13,[27][28][29] Some aspects emerge as new: in particular, the significant association between hepatoblastoma and UPD may have relevant implications for cancer screening, the association between IC2-GoM and uretheral defects and polyhydramnios may have implications for the neonatal nephrourological management, the higher incidence of benign neoplasm paralleling the distribution of the malignant ones should be taken into considerations during patients' follow-up. Finally, IC2-LoM/CDKN1C variant patients display a higher rate of postnatal overgrowth, poorly studied before; as in these molecular subgroups neonatal macrosomia is rarer than in UPD/IC1-GoM ones 13 clinicians should be aware that these molecular subtypes of BWS may display specific growth patterns after the neonatal period.…”

Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders

“…Loss of methylation (LOM) at ICR1 accounts for over 50% of SRS cases, while gain of methylation (GOM) at ICR1 and LOM at ICR2 trigger BWS in approximately 10% and 60% of cases, respectively. In addition, maternal uniparental disomy of chromosome 7 (mUPD7) and paternal UPD of 11p15.5 are present in 7–10% of SRS and 20% of BWS, respectively [3–5]. …”

The Frequency of Methylation Abnormalities Among Estonian Patients Selected by Clinical Diagnostic Scoring Systems for Silver–Russell Syndrome and Beckwith–Wiedemann Syndrome

“…This is one of the main aims of the European Network of Congenital Imprinting Disorders (www.imprinting-disorders.eu) in the nearest future to help clinicians recognize and diagnose both syndromes and select the candidates for further molecular studies in everyday practice. Recently, more simple and objective scoring systems were published (Dias et al, 2013;Ibrahim et al, 2014). These scoring systems do not focus on subjective features.…”

“…We did not have any preselection and we studied all the referred patients, as there exists a recommendation for both syndromes to look for imprinting disorders in every patient with a suspicion of SRS or BWS, even if the clinical picture is incomplete. Although over the years, many clinical criteria and scoring systems for diagnosis of SRS and BWS have been revised and suggested (see for review Tables 4 and 5) (Elliott and Maher, 1994;Lai et al, 1994;DeBaun and Tucker, 1998;Price et al, 1999;Netchine et al, 2007;Bartholdi et al, 2009;Weksberg et al, 2010;Dias et al, 2013;Ibrahim et al, 2014), neither syndrome has common consensus diagnostic criteria yet. This is one of the main aims of the European Network of Congenital Imprinting Disorders (www.imprinting-disorders.eu) in the nearest future to help clinicians recognize and diagnose both syndromes and select the candidates for further molecular studies in everyday practice.…”