Prenatal molecular testing and diagnosis of Beckwith-Wiedemann syndrome

The objective of this study was to describe molecular findings and phenotypic features among individuals referred for prenatal Beckwith-Wiedemann syndrome (BWS) testing.

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.

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.

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.