Abstract for presentation at 11th International Congress of Human Genetics

Familial overgrowth and Wilms tumor associated with paternally inherited duplication on chromosome 11p15.5

  • Dr Elizabeth Algar, Iniversity of Melbourne and the Murdoch Children's Research Insititute, Australia
  • Mr Luke St Heaps, The Children's Hospital at Westmead, Australia
  • Dr Greg Peters, The Children's Hospital at Westmead, Australia
  • Dr Dirk Prawitt, University of Mainz, Germany
  • Dr Felicity Collins, The Children's Hospital at Westmead, Australia

    • Beckwith Wiedemann Syndrome (BWS) is an overgrowth disorder typically presenting with pre and post-natal overgrowth, macroglossia and abdominal wall defects. Recent definition of several molecular sub-groups has enabled the risk for Wilms tumors in BWS children to be predicted with greater certainty. 5% of patients have epimutations affecting Imprinting Centre 1( IC1) at the IGF2/H19 locus on 11p15.5 and these patients , along with the 15% of patients with paternal UPD 11p15.5, are at high risk for developing Wilms tumor. In contrast, Wilms tumor has not been reported in patients with an 11p15.5 IC2 epimutation.
    We have studied a three-generation family with prenatal onset of a generalized overgrowth disorder and Wilms tumor. The proband
    presented with bilateral Wilms tumours at age 19 months. A younger sister was diagnosed with bilateral Wilms at age 5 months and the father developed unilateral Wilms tumour at age 30 months. There were no other features of BWS. High resolution karyotype and 11p subtelomere FISH were normal.
    Three generations of the family were investigated. Allelotyping on 11p15 revealed co-inheritance of a common paternal haplotype in the affected but not in the unaffected individuals and revealed a sub-region of allelic imbalance, in 2:1 ratio (paternal : maternal ) localized to the TH locus, but excluding D11S4088 proximally and D11S922 distally. Methylation analysis at IC1 revealed evidence for mosaic gain of methylation, whereas IC2 was normal. Taken together, these results suggest a submicroscopic paternal duplication at 11p15.5 including the IGF2/H19 locus in the affected individuals. SNP arrays are presently being used to determine the size of the duplicated region. This study has shown that in some patients with combined overgrowth, Wilms tumor and partial gain of methylation at IC1, the underlying mutation may involve a paternal duplication of IC1, rather than mosaic hypermethylation.This further supports a critical role for increased IGF2 dosage in Wilms tumor.

    Conference Organiser - ICMS Pty Ltd