The Contribution of Whole Gene Deletions and Large Rearrangements to the Mutation Spectrum in Inherited Tumor Predisposing Syndromes.

Miriam J Smith, Jill Urquhart, Elaine Harkness, Emma K Miles, Naomi L Bowers, Helen Byers, Michael Bulman, Carolyn Gokhale, Andrew J Wallace, William Newman, Gareth Evans

Research output: Contribution to journalArticlepeer-review

Abstract

Heterozygous whole gene deletions (WGDs), and intragenic microdeletions, account for a significant proportion of mutations underlying cancer pre-disposition syndromes. We analysed the frequency and genotype-phenotype correlations of microdeletions in twelve genes (BRCA1, BRCA2, TP53, MSH2, MLH1, MSH6, PMS2, NF1, NF2, APC, PTCH1 and VHL) representing seven tumor predisposition syndromes in 5897 individuals (2611 families) from our Centre. Overall, microdeletions accounted for 14% of identified mutations. As expected, smaller deletions or duplications were more common (12%) than WGDs (2.2%). Where a WGD was identified in the germline in NF2, the mechanism of somatic second hit was not deletion, as previously described for NF1. For neurofibromatosis type 1 and 2, we compared the mechanism of germline deletion. Unlike NF1, where three specific deletion sizes account for most germline WGDs, NF2 deletion breakpoints were different across seven samples tested. One of these deletions was 3.93 Mb and conferred a severe phenotype, thus refining the region for a potential NF2 modifier gene to a 2.04 Mb region on chromosome 22. The milder phenotype of NF2 WGDs may be due to the apparent absence of chromosome 22 loss as the second hit. These observations of WGD phenotypes will be helpful for interpreting incidental findings from microarray analysis and next generation sequencing. This article is protected by copyright. All rights reserved.
Original languageEnglish
Pages (from-to)250–256
JournalHuman Mutation
Volume37
Issue number3
Early online date30 Nov 2015
DOIs
Publication statusPublished - Mar 2016

Keywords

  • Breast cancer
  • Familial adenomatous polyposis
  • Gorlin syndrome
  • Lynch syndrome
  • Neurofibromatosis
  • Whole gene deletion
  • von Hippel Lindau

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