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Map of the BWS locus on 11p15.5
a) A schematic representation of the normal parent of origin-specific imprinted allelic expression. Note: b) and c) show the altered region only. The image is not drawn to scale.
Cen = centromere; DMR = differentially methylated region; IC = imprinting center; M = maternal; OT1 = KCNQ1 antisense transcript, KCNQ1OT1; P = paternal; Tel = telomere
Republished with permission from Choufani et al [2010]

Causes of Beckwith-Wiedemann syndrome by genetic mechanism
* These molecular subgroups, defined by DNA methylation abnormalities, may also be the result of an underlying genomic alteration. Such genomic aberrations are most common for hypermethylation of IC1 and least common for hypomethylation at IC2. Genomic aberrations, limited to the BWS critical region on chromosome 11p15.5, can be detected by MS-MLPA or various sequencing technologies. Some deletions/duplications may be detected by CMA.
BWS = Beckwith-Wiedemann syndrome; CMA = chromosomal microarray; IC1 = imprinting center 1; IC2 = imprinting center 2; MS-MLPA = methylation-specific multiplex ligation-dependent probe amplification

Flowchart for molecular diagnosis of Beckwith-Wiedemann syndrome
Recommended first-line testing (highlighted in orange) analyzes methylation at H19/IGF2:IG DMR (IC1) and KCNQ1OT1:TSS DMR (IC2) and copy number variation (CNV). These tests can yield positive molecular diagnoses of chromosome 11 abnormalities, paternal uniparental disomy of chromosome 11 (pUPD), IC1 gain of methylation (IC1 GOM), and IC2 loss of methylation (IC2 LOM) (highlighted in dark green). Further testing (highlighted in blue) can determine chromosomal abnormalities more precisely. If DNA methylation testing is normal, CDKN1C sequencing and/or additional tests for rare chromosomal translocations are recommended. Normal test results can also be due to tissue mosaicism (in which the genetic alteration may not be found due to absence of the molecular change in the tissue sampled), and additional tissue samples can be tested.
Adapted from Wang et al [2020]