1. Figure 2 Flowchart for investigation and diagnosis of Beckwith– Wiedemann syndrome
Figure 2 | Flowchart for investigation and diagnosis of Beckwith– Wiedemann syndrome. The figure summarizes the molecular diagnostic pathway for investigation of suspected Beckwith–Wiedemann spectrum (BWSp). Patients with clinical features reaching a score of ≥2 should be genetically tested. It is recommended that first-line testing should assay the methylation status of H19/IGF2:intergenic (IG) differentially methylated region (DMR) (also known as IC1) and KCNQ1OT1:transcriptional start site (TSS) DMR (also known as IC2). If not estimated simultaneously with DNA methylation, DMR copy number should then be determined in all patients with IC1 and/or IC2 methylation abnormalities. These assays can yield positive molecular diagnosis of BWSp with IC2 loss of methylation (LOM), IC1 gain of methylation (GOM), segmental paternal uniparental isodisomy (UPD) of 11p15.5 (upd(11)pat) or copy number variation (CNV; most commonly duplication of paternal 11p15.5 (dup(11)(p15.5)pat)). Further molecular tests can be considered to determine underlying mechanism of methylation abnormality, UPD or CNV. If DNA methylation testing is negative, further molecular tests can be considered to identify mosaic methylation abnormalities, pathogenic CDKN1C variants or rare balanced chromosomal rearrangements. If all molecular tests are negative, differential diagnosis should be considered. However, a diagnosis of classical Beckwith–Wiedemann syndrome (BWS) is made in the presence of a clinical score of ≥4 even in the absence of the molecular confirmation of an 11p15 anomaly. CMA, chromosome microarray analysis (can be oligonucleo­tide-based and/or single-nucleotide-polymorphism-based platforms); FISH, fluorescence in situ hybridization; LOF, loss of function; MLPA, multiplex ligation-dependent probe amplification; SNP, single nucleotide polymorphism; SNV, single nucleotide variation. *CNV status may be determined simultaneously with methylation testing. ‡See main text for indications for testing. §Deletion of maternal 11p15.5 (del(11)(p15.5)mat) may be detected with lower frequency.
Brioude, F. et al. (2018) Clinical and molecular diagnosis, screening and management of Beckwith–Wiedemann syndrome: an international consensus statement Nat. Rev. Endocrinol. doi: /nrendo