Abstract
Beckwith-Wiedemann syndrome (BWS) is a clinically and genetically heterogeneous overgrowth disease. BWS is caused by (epi)genetic defects at the 11p15 chromosomal region, which harbors two clusters of imprinted genes, IGF2/H19 and CDKN1C/KCNQ1OT1, regulated by differential methylation of imprinting control regions, H19/IGF2:IG DMR and KCNQ1OT1:TSS DMR, respectively. A subset of BWS patients show multi-locus imprinting disturbances (MLID), with methylation defects extended to other imprinted genes in addition to the disease-specific locus. Specific (epi)genotype-phenotype correlations have been defined in order to help clinicians in the classification of patients and referring them to a timely diagnosis and a tailored follow-up. However, specific phenotypic correlations have not been identified among MLID patients, thus causing a debate on the usefulness of multi-locus testing in clinical diagnosis. Finally, the high incidence of BWS monozygotic twins with discordant phenotypes, the high frequency of BWS among babies conceived by assisted reproductive technologies, and the female prevalence among BWS-MLID cases provide new insights into the timing of imprint establishment during embryo development. In this review, we provide an overview on the clinical and molecular diagnosis of single- and multi-locus BWS in pre- and post-natal settings, and a comprehensive analysis of the literature in order to define possible (epi)genotype-phenotype correlations in MLID patients.
Highlights
Aberrant methylation levels at a single imprinting control regions (ICs) are indicative of a primary epimutation or, rarely, of copy number variants (CNVs), while the identification of both IC1 Gain of methylation (GOM) and IC2 loss of methylation (LOM) may be associated with segmental pUPD11
New relevant knowledge has emerged regarding the multi-locus pattern of the epigenetic alterations, which opens up new avenues of investigation at genomic level
No specific clinical signs are probably present in multi-locus imprinting disturbances (MLID), we observed that
Summary
First described by Beckwith in 1963 and Wiedemann in 1964, BWS shows clinical and genetic heterogeneity It is a pan-ethnic condition, with an estimated incidence of 1:10,000–13,700 live births [1,2] and an overall equal incidence in males and females, except for monozygotic twins, in which there is a female prevalence. BWS is caused by different epigenetic or genetic defects that alter the expression of known imprinted genes mapping at the 11p15 chromosomal region. This region harbors two imprinted domains, IGF2/H19 and CDKN1C/KCNQ1OT1, regulated by the differential methylation in the two imprinting control regions (ICs), namely H19/IGF2:IG DMR (IC1) and KCNQ1OT1:TSS. We provide an overview on the clinical and molecular diagnosis of single- and multi-locus BWS in a pre- and post-natal setting, by a comprehensive analysis of the literature data in order to further explore (epi)genotype-phenotype correlations in MLID patients compared with those with single-locus alterations
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