Figure 2.

Diagnostic flowchart for BWS according to the BWSp scoring system [51]. Only patients with a diagnostic score ≥2 should receive molecular testing. Molecular testing, reported in grey boxes, should always start with a methylation analysis of IC1 and IC2, and in case of a positive result, it should always be followed by a copy number variant (CNV) assessment. A positive result (light blue boxes) of methylation analysis may derive from a primary epimutation at ICs (IC2 LOM or IC1 GOM) or pUPD11 (both IC2 LOM and IC1 GOM). SNP array may confirm pUPD11. Patients negative at methylation evaluation and CNV testing should undergo CDKN1C mutational analysis. In patients with IC2 LOM MLID methylation analysis and whole-exome sequencing for the identification of MLID causative mutations can be performed for research purposes. Negative results at all standard BWS testing may be due to tissue mosaicism and, in these cases, the analysis of tissue samples other than blood is mandatory. Differential diagnosis should be considered and appropriate tests performed. Patients with negative results for all the analyses, but with a clinical score ≥4, have a clinical diagnosis of BWS without a molecular evidence (adapted from [53]).