Exome sequencing of familial adenomatous polyposis-like individuals identifies both known and novel causative genes

Clin Genet. 2021 Oct;100(4):478-483. doi: 10.1111/cge.14029. Epub 2021 Jul 26.


Inherited polyposis syndromes are predominantly caused by pathogenic variants in APC and are linked to familial adenomatous polyposis (FAP). However, after clinical screening, 20%-30% of individuals diagnosed with FAP do not carry a pathogenic variant in APC (often categorised as FAP-like). Other known inherited adenomatous polyposis syndromes such as MUTYH, POLD1/E, or NTHL1-associated polyposis only account for, 3 a fraction of the remaining cases. A cohort of 48 individuals clinically diagnosed with a FAP-like phenotype was selected based on a strong family history of colorectal cancer and no previous pathogenic variant found in APC and/or MUTYH, by genetic screening. Using whole exome sequencing, FAP-like patients were found to carry pathogenic variants in MUTYH, APC, POLE and TP53, as well as DNA-repair genes and inflammation related genes. Additionally, a comprehensive assessment of copy number variation revealed two loci of interest that appeared to be associated with polyposis risk. In total, 6 out of 48 polyposis were explained through re-sequencing. This study highlights the potential role of DNA-repair as well as inflammation-related variants towards polyp development.

Keywords: colorectal cancer; familial cancer; inherited cancer; polyposis; sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / diagnosis*
  • Adenomatous Polyposis Coli / genetics*
  • Alleles*
  • Amino Acid Substitution
  • DNA Copy Number Variations
  • DNA Glycosylases / genetics
  • Exome Sequencing*
  • Genes, APC
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Humans
  • Mutation
  • Phenotype*
  • Sequence Analysis, DNA


  • DNA Glycosylases
  • mutY adenine glycosylase

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