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Original research
Improved molecular detection of mosaicism in Beckwith-Wiedemann Syndrome
  1. Samuel W Baker1,
  2. Kelly A Duffy2,
  3. Jennifer Richards-Yutz1,
  4. Matthew A Deardorff2,3,
  5. Jennifer M Kalish2,3,
  6. Arupa Ganguly1
  1. 1Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  2. 2Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  3. 3Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Arupa Ganguly, Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; ganguly{at}; Dr Jennifer M Kalish, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; kalishj{at}


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.

  • genetics
  • diagnostics
  • imprinting
  • clinical genetics
  • epigenetics
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  • Contributors SWB, KAD, MD, JMK and AG planned the study. SWB, KAD and JR-Y analysed data. SWB, JMK and AG wrote the manuscript. JMK and AG supervised the study.

  • Funding This work was supported by the National Institute of Health K08 CA193915 (JMK), Alex’s Lemonade Stand Foundation (JMK) and St Baldrick’s Foundation (JMK).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was deemed exempt from IRB approval, as based on the Office of Human Research Protections Human Subject Decision Charts.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Study data are available on reasonable request.

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