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Should testing for mosaic genome-wide paternal uniparental disomy in Beckwith-Wiedemann spectrum (BWSp) be implemented in diagnostic testing?

European Journal of Human Genetics volume 31, pages 615–616 (2023)Cite this article

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Beckwith-Wiedemann syndrome (BWS; OMIM #130650), is an overgrowth disorder mainly characterized by macrosomia, macroglossia, and abdominal wall defects. Diagnosis is made based on a clinical scoring system and because the phenotype can be variable the term Beckwith-Wiedemann spectrum (BWSp) is recently introduced [1]. Approximately 80–85% of the clinically diagnosed patients have (epi)genetic aberrations in the imprinting center regions ICR1 and ICR 2 on 11p.15 leading to the perturbed expression of monoallelic expressed (imprinted) genes. There are three most common molecular subtypes: loss of methylation at KCNQ1OT1:TSS-DMR (IC2 LOM; ~50% of patients), gain of methylation at H19/IGF2:IG-DMR (IC1 GOM; 5–10% of patients), and paternal uniparental isodisomy of chromosome 11 (patUPD11; ~20% of patients). A small number of patients have an intragenic mutation in the CDKN1C gene. In ~15% of BWS cases, no (epi)genetic aberrations in the primary BWS-associated region 11p15 can be detected [1]. In these patients molecular testing in other tissues can be considered as somatic mosaicism can vary between different tissues [1, 2].

Patients with BWSp have an increased risk of developing embryonal tumors depending on the genetic subgroup. Patients with pUPD11 have an overall tumor risk of 16%, mainly Wilms tumor (7.9%) and hepatoblastoma (3.5%) [1, 3]. With some differences in mean age at diagnosis depending on tumor types, the overall cancer risk is highest in the first 2 years of life and then declines progressively. Therefore tumor screening until the age of seven is carried out in all genetic subgroups except IC2LOM, who are not screened at all [1].

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This viewpoint article received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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Author notes

  1. These authors contributed equally: Saskia M. Maas, Izabela M. Krzyzewska.

Authors and Affiliations

  1. Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Saskia M. Maas, Izabela M. Krzyzewska, Maria P. R. Lombardi, Marcel M. A. Mannens, Niels Vos & Jet Bliek

  2. European Reference Network for Rare Craniofacial Anomalies and ENT Disorders (ERN CRANIO), Amsterdam, The Netherlands

    Saskia M. Maas

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Contributions

SMM and IMK designed and wrote the manuscript; MPRL, NV, MMAM and JB were essential for the discussion on the topic of MGWpatUPD in BWSp and provided feedback on the manuscript.

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Correspondence to Jet Bliek.

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Maas, S.M., Krzyzewska, I.M., Lombardi, M.P.R. et al. Should testing for mosaic genome-wide paternal uniparental disomy in Beckwith-Wiedemann spectrum (BWSp) be implemented in diagnostic testing?. Eur J Hum Genet 31, 615–616 (2023). https://doi.org/10.1038/s41431-023-01354-4

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