Prenatal molecular testing and diagnosis of Beckwith‐Wiedemann syndrome

• Published in: Prenatal diagnosis 2021-06, Vol.41 (7), p.817-822
• Main Authors: Baker, Samuel W., Ryan, Elyse, Kalish, Jennifer M., Ganguly, Arupa
• Format: Article
• Language: English
• Subjects: Adult; Beckwith-Wiedemann Syndrome - diagnosis; Cyclin-Dependent Kinase Inhibitor p57 - analysis; Cyclin-Dependent Kinase Inhibitor p57 - isolation & purification; Diagnosis; Female; Humans; Medical diagnosis; Methylation; Molecular Diagnostic Techniques - methods; Molecular Diagnostic Techniques - statistics & numerical data; Pregnancy; Prenatal Diagnosis - methods; Prenatal Diagnosis - trends
• ISSN: 0197-3851; 1097-0223
• DOI: 10.1002/pd.5953

Objective The objective of this study was to describe molecular findings and phenotypic features among individuals referred for prenatal Beckwith‐Wiedemann syndrome (BWS) testing. Methods Molecular diagnostic testing was performed using a sensitive quantitative real‐time PCR‐based assay capable of detecting mosaic methylation to the level of 3% at IC1 and IC2. Sanger sequencing of CDKN1C was performed in cases with normal methylation. Results Of the 94 patients tested, a molecular diagnosis was identified for 25.5% of cases; 70.9% of diagnosed cases had loss of methylation at IC2, 4.2% had gain of methylation at IC1, 12.5% had paternal uniparental isodisomy, and 12.5% had CDKN1C loss‐of‐function variants. Methylation level changes in prenatal cases were significantly greater than changes identified in cases tested after birth. Cases with a prenatal molecular diagnosis had a significantly greater number of BWS‐associated phenotypic features. The presence of either macroglossia or placentomegaly was most predictive of a BWS diagnosis. Conclusion Our results support the consensus statement advocating BWS molecular testing for all patients with one or more BWS‐associated prenatal features and suggest that low‐level mosaic methylation changes may be uncommon among prenatal BWS diagnoses. Key Points What is already known about this topic? Prenatal features and molecular findings associated with prenatal diagnosis of BWS have been previously described in multiple publications. What does this study add? This study demonstrates the use of an assay with improved mosaic detection for BWS in a prenatal cohort of patients. We report which prenatal features are predictive of a diagnosis in our cohort.