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Constitutional UPD for chromosome 11p15 in individuals with isolated hemihyperplasia is associated with high tumor risk and occurs following assisted reproductive technologies

Authors

  • Cheryl Shuman,

    1. Division of Clinical & Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada
    2. The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
    3. Department of Molecular & Medical Genetics, University of Toronto, Toronto, Ontario, Canada
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  • Adam C. Smith,

    1. The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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  • Leslie Steele,

    1. Department of Molecular & Medical Genetics, University of Toronto, Toronto, Ontario, Canada
    2. Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Peter N. Ray,

    1. The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Department of Molecular & Medical Genetics, University of Toronto, Toronto, Ontario, Canada
    3. Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Carol Clericuzio,

    1. Pediatrics-Division of Dysmorphology/Clinical Genetics, University of New Mexico School of Medicine, Albuquerque, New Mexico
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  • Elaine Zackai,

    1. Division of Human Genetics & Molecular Biology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
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  • Melissa A. Parisi,

    1. Division of Genetics and Developmental Medicine, University of Washington, Seattle, Washington
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  • Anna T. Meadows,

    1. Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
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  • Thaddeus Kelly,

    1. Department of Pediatric Genetics, UVA Health System, Charlottesville, Virginia
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  • David Tichauer,

    1. Division of Clinical & Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Jeremy A. Squire,

    1. Department of Lab Medicine & Pathobiology and Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada
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  • Paul Sadowski,

    1. Department of Molecular & Medical Genetics, University of Toronto, Toronto, Ontario, Canada
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  • Rosanna Weksberg

    Corresponding author
    1. Division of Clinical & Metabolic Genetics, Hospital for Sick Children, Toronto, Ontario, Canada
    2. The Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada
    3. Department of Molecular & Medical Genetics, University of Toronto, Toronto, Ontario, Canada
    4. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
    • Clinical and Metabolic Genetics, The Hospital for Sick Children, 555 University Ave., Toronto, Ont., Canada M5G 1X8.
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  • How to cite this article: Shuman C, Smith AC, Steele L, Ray PN, Clericuzio C, Zackai E, Parisi MA, Meadows AT, Kelly T, Tichauer D, Squire JA, Sadowski P, Weksberg R. 2006. Constitutional UPD for chromosome 11p15 in individuals with isolated hemihyperplasia is associated with high tumor risk and occurs following assisted reproductive technologies. Am J Med Genet Part A 140A:1497–1503.

Abstract

Isolated hemihyperplasia (IH) refers to a distinct diagnosis involving asymmetric overgrowth of single or multiple organs or regions of the body and can result from various genomic changes including molecular alterations of 11p15; these are paternal uniparental disomy (UPD), and alterations of methylation at two imprinting centers at 11p15: IC1 (H19) and IC2 (KCNQ1OT1). As little information is available on the molecular basis of tumor development in IH, or on the frequency of tumors in children with different molecular subtypes of IH, molecular testing was undertaken on 51 patients with IH and revealed: 8 (16%) with UPD, 3 (6%) with hypomethylation at KCNQ1OT1, and 0 with hypermethylation at H19. Of the 8 patients with UPD, 4 had tumors (3 hepatoblastomas, 1 Wilms tumor); 0/3 patients with hypomethylation at KCNQ1OT1 had a tumor; of the remaining 40 with no molecular alterations, 6 had tumors (3 Wilms tumors, 2 neuroblastomas, 1 adrenocortical adenoma). The 50% tumor frequency in patients with IH and UPD was statistically significantly higher than the 15% tumor frequency in those with IH and no molecular alteration detected (Fisher's exact test P = 0.047, OR 5.67). This is the first demonstration that UPD at 11p15 in patients with IH confers a higher tumor risk than in patients with IH without this molecular change. Of note, two of the eight patients with UPD and IH were conceived using assisted reproductive technologies (ART), thus raising the question whether ART might impact the rate of somatic recombination during embryonic development. © 2006 Wiley-Liss, Inc.

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