A novel APC promoter 1B deletion shows a founder effect in Italian patients with classical familial adenomatous polyposis phenotype

Monica Marabelli, Viviana Gismondi, Maria Teresa Ricci, Annalisa Vetro, Raefa Abou Khouzam, Valentina Rea, Marco Vitellaro, Orsetta Zuffardi, Liliana Varesco, Guglielmina Nadia Ranzani

Research output: Contribution to journalArticlepeer-review


Familial adenomatous polyposis is a Mendelian syndrome in which germline loss-of-function mutations of APC are associated with multiple adenomatous polyps of the large bowel, a multiplicity of extracolonic features, and a high lifetime risk of colorectal cancer. Different APC germline mutations have been identified, including sequence changes, genomic rearrangements, and expression defects. Recently, very rare families have been associated with constitutive large deletions encompassing the APC-5' regulatory region, while leaving the remaining gene sequence intact; the regulatory region contains a proximal and a distal promoter, called 1A and 1B, respectively. We identified a novel deletion encompassing promoter 1B in a large Italian family that manifested polyposis in three of the six branches descending from a founding couple married in 1797. By combining different molecular approaches on both DNA and RNA, we precisely mapped this deletion (6858 bp in length) that proved to be associated with APC allele silencing. The finding of the same deletion in two additional polyposis families pointed to a founder mutation in Italy. Deletion carriers from the three families all showed a "classical" polyposis phenotype. To explore the molecular mechanisms underlying promoter deletions, we performed an in silico analysis of the breakpoints of 1A and 1B rearrangements so far reported in the literature; moreover, to decipher genotype-phenotype correlations, we critically reviewed current knowledge on deletions versus point mutations in the APC-5' regulatory region.

Original languageEnglish
Pages (from-to)846-854
Number of pages9
JournalGenes Chromosomes and Cancer
Issue number12
Publication statusPublished - Dec 2017


  • Adenomatous Polyposis Coli
  • Adenomatous Polyposis Coli Protein
  • Adolescent
  • Adult
  • Female
  • Founder Effect
  • Gene Deletion
  • Germ-Line Mutation
  • Humans
  • Italy
  • Male
  • Middle Aged
  • Pedigree
  • Phenotype
  • Promoter Regions, Genetic
  • Journal Article


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