Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Mar;58(3):178-184.
doi: 10.1136/jmedgenet-2019-106498. Epub 2020 May 19.

Improved molecular detection of mosaicism in Beckwith-Wiedemann Syndrome

Samuel W Baker  1 , Kelly A Duffy  2 , Jennifer Richards-Yutz  1 , Matthew A Deardorff  2   3 , Jennifer M Kalish  4   3 , Arupa Ganguly  5
Affiliations

Improved molecular detection of mosaicism in Beckwith-Wiedemann Syndrome

Samuel W Baker et al. J Med Genet. 2021 Mar.

Abstract

Background: Beckwith-Wiedemann Syndrome (BWS) is characterised by overgrowth and tumour predisposition. While multiple epigenetic and genetic mechanisms cause BWS, the majority are caused by methylation defects in imprinting control regions on chromosome 11p15.5. Disease-causing methylation defects are often mosaic within affected individuals. Phenotypic variability among individuals with chromosome 11p15.5 defects and tissue mosaicism led to the definition of the Beckwith-Wiedemann Spectrum (BWSp). Molecular diagnosis of BWSp requires use of multiple sensitive diagnostic techniques to reliably detect low-level aberrations.

Methods: Multimodal BWS diagnostic testing was performed on samples from 1057 individuals. Testing included use of a sensitive qRT-PCR-based quantitation method enabling identification of low-level mosaic disease, identification of CNVs within 11p15.5 via array comparative genomic hybridisation or qRT-PCR, and Sanger sequencing of CDKN1C.

Results: A molecular diagnosis was confirmed for 27.4% of individuals tested, of whom 43.4% had mosaic disease. The presence of a single cardinal feature was associated with a molecular diagnosis of BWSp in 20% of cases. Additionally, significant differences in the prevalence of mosaic disease among BWS molecular subtypes were identified. Finally, the diagnostic yield obtained by testing solid tissue samples from individuals with negative blood testing results shows improved molecular diagnosis.

Conclusion: This study highlights the prevalence of mosaic disease among individuals with BWSp and the increases in diagnostic yield obtained via testing both blood and solid tissue samples from affected individuals. Additionally, the results establish the presence of a molecular diagnosis in individuals with very subtle features of BWSp.

Keywords: clinical genetics; diagnostics; epigenetics; genetics; imprinting.

PubMed Disclaimer

Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Chromosome 11p15.5 Beckwith-Wiedemann Syndrome locus.This locus is divided into two distinct regions, termed IC1 and IC2, each of which contains multiple imprinted genes. Filled/unfilled boxes represent genes and the direction of transcription is indicated by arrows above gene boxes. The direction of antisense transcription is represented by arrows below gene boxes. Note, this locus is not drawn to scale.
Figure 2
Figure 2
Mosaic methylation findings. (A) Distribution of measured mosaic methylation defects among BWS molecular subtypes. Normal n=100. IC2 LOM n=126, IC2 GOM n=45, upd(11)pat n=48. (B) Prevalence of mosaic methylation defects among BWS molecular subtypes. ***P<0.0001. BWS, Beckwith-Wiedemann Syndrome.
Figure 3
Figure 3
Summary of diagnostic findings. (A) Diagnostic yield of testing 1057 individuals, (B) breakdown of molecular diagnoses by defect molecular subtype.
Figure 4
Figure 4
Factors influencing diagnostic yield. (A) Diagnostic yield by number of clinical features indicated on requisition form, (B) diagnostic yield by sample types tested. ***P<0.0001.
See this image and copyright information in PMC

References

    1. Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, Boonen SE, Cole T, Baker R, Bertoletti M, Cocchi G, Coze C, De Pellegrin M, Hussain K, Ibrahim A, Kilby MD, Krajewska-Walasek M, Kratz CP, Ladusans EJ, Lapunzina P, Le Bouc Y, Maas SM, Macdonald F, Õunap K, Peruzzi L, Rossignol S, Russo S, Shipster C, Skórka A, Tatton-Brown K, Tenorio J, Tortora C, Grønskov K, Netchine I, Hennekam RC, Prawitt D, Tümer Z, Eggermann T, Mackay DJG, Riccio A, Maher ER. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol 2018;14:229–49. - PMC - PubMed
    1. Choufani S, Shuman C, Weksberg R. Beckwith-Wiedemann syndrome. Am J Med Genet C Semin Med Genet 2010;154C:343–54. - PubMed
    1. Eggermann T, Perez de Nanclares G, Maher ER, Temple IK, Tümer Z, Monk D, Mackay DJG, Grønskov K, Riccio A, Linglart A, Netchine I. Imprinting disorders: a group of congenital disorders with overlapping patterns of molecular changes affecting imprinted loci. Clin Epigenetics 2015;7:123. - PMC - PubMed
    1. Azzi S, Abi Habib W, Netchine I, Beckwith-Wiedemann NI. Beckwith-Wiedemann and Russell-Silver syndromes: from new molecular insights to the comprehension of imprinting regulation. Curr Opin Endocrinol Diabetes Obes 2014;21:30–8. - PubMed
    1. Eggermann T, Algar E, Lapunzina P, Mackay D, Maher ER, Mannens M, Netchine I, Prawitt D, Riccio A, Temple IK, Weksberg R. Clinical utility gene card for: Beckwith-Wiedemann syndrome. Eur J Hum Genet 2014;22. - PMC - PubMed

Publication types

MeSH terms

Substances