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High frequency of copy number variations (CNVs) in the chromosome 11p15 region in patients with Beckwith–Wiedemann syndrome

Human Genetics volume 133, pages 321–330 (2014)Cite this article

Abstract

Beckwith–Wiedemann syndrome (BWS), an overgrowth and tumor predisposition syndrome is clinically heterogeneous. Its variable presentation makes molecular diagnosis particularly important for appropriate counseling of patients with respect to embyronal tumor risk and recurrence risk. BWS is characterized by macrosomia, omphalocele, and macroglossia. Additional clinical features can include hemihyperplasia, embryonal tumors, umbilical hernia, and ear anomalies. BWS is etiologically heterogeneous arising from dysregulation of one or both of the chromosome 11p15.5 imprinting centers (IC) and/or imprinted growth regulatory genes on chromosome 11p15.5. Most BWS cases are sporadic and result from loss of maternal methylation at imprinting center 2 (IC2), gain of maternal methylation at imprinting center 1 (IC1) or paternal uniparental disomy (UPD). Heritable forms of BWS (15 %) have been attributed mainly to mutations in the growth suppressor gene CDKN1C, but have also infrequently been identified in patients with copy number variations (CNVs) in the chromosome 11p15.5 region. Four hundred and thirty-four unrelated BWS patients referred to the molecular diagnostic laboratory were tested by methylation-specific multiplex ligation-dependent probe amplification. Molecular alterations were detected in 167 patients, where 103 (62 %) showed loss of methylation at IC2, 23 (14 %) had gain of methylation at IC1, and 41 (25 %) showed changes at both ICs usually associated with paternal UPD. In each of the three groups, we identified patients in whom the abnormalities in the chromosome 11p15.5 region were due to CNVs. Surprisingly, 14 patients (9 %) demonstrated either deletions or duplications of the BWS critical region that were confirmed using comparative genomic hybridization array analysis. The majority of these CNVs were associated with a methylation change at IC1. Our results suggest that CNVs in the 11p15.5 region contribute significantly to the etiology of BWS. We highlight the importance of performing deletion/duplication testing in addition to methylation analysis in the molecular investigation of BWS to improve our understanding of the molecular basis of this disorder, and to provide accurate genetic counseling.

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Authors and Affiliations

  1. The Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden

    Berivan Baskin

  2. The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada

    Berivan Baskin & Dimitri J. Stavropoulos

  3. Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada

    Sanaa Choufani, Yi-an Chen, Cheryl Shuman, Peter N. Ray & Rosanna Weksberg

  4. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Yi-an Chen & Rosanna Weksberg

  5. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada

    Cheryl Shuman, Nicole Parkinson & Rosanna Weksberg

  6. Department of Molecular Genetics, The University of Toronto, Toronto, ON, Canada

    Cheryl Shuman, Peter N. Ray & Rosanna Weksberg

  7. Division of Molecular Genetics, The Hospital for Sick Children, Toronto, ON, Canada

    Nicole Parkinson, Dimitri J. Stavropoulos & Peter N. Ray

  8. Medical Genetics Service, Department of Pediatrics, CHU Sainte-Justine, Montreal, QC, Canada

    Emmanuelle Lemyre

  9. Department of Medical Genetics, Faculty of Medicine, University of Calgary, Calgary, AB, Canada

    A. Micheil Innes

  10. Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada

    Dimitri J. Stavropoulos

  11. Department of Paediatrics, University of Toronto, Toronto, ON, Canada

    Rosanna Weksberg

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  1. Berivan Baskin
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  2. Sanaa Choufani
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  3. Yi-an Chen
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  4. Cheryl Shuman
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  5. Nicole Parkinson
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  7. A. Micheil Innes
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  8. Dimitri J. Stavropoulos
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  9. Peter N. Ray
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  10. Rosanna Weksberg
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Correspondence to Rosanna Weksberg.

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Baskin, B., Choufani, S., Chen, Ya. et al. High frequency of copy number variations (CNVs) in the chromosome 11p15 region in patients with Beckwith–Wiedemann syndrome. Hum Genet 133, 321–330 (2014). https://doi.org/10.1007/s00439-013-1379-z

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  • DOI: https://doi.org/10.1007/s00439-013-1379-z

Keywords

  • Chromosome 11p15
  • Genomic Alteration
  • Methylation Alteration
  • CTCF Binding Site
  • Comparative Genomic Hybridization Array Analysis