Exome Sequencing Reveals Germline SMAD9 Mutation That Reduces Phosphatase and Tensin Homolog Expression and Is Associated With Hamartomatous Polyposis and Gastrointestinal Ganglioneuromas

Gastroenterology. 2015 Oct;149(4):886-9.e5. doi: 10.1053/j.gastro.2015.06.027. Epub 2015 Jun 26.


Hamartomatous polyposis syndromes (HPS) account for a small but appreciable proportion of inherited gastrointestinal cancer predisposition syndromes; patients with HPS have an increased risk for colon and extracolonic malignancies. We present a unique case of familial juvenile polyposis syndrome associated with gastrointestinal ganglioneuromas of unknown etiology. The patient was tested for HPS-associated genes, but no mutation was detected. Exome sequencing identified a germline heterozygous mutation in SMAD9 (SMAD9(V90M)). This mutation was predicted to be an activating mutation. HEK cells transfected to express SMAD9(V90M) had reduced expression of phosphatase and tensin homolog; this reduction was also observed in a polyp from the patient. We have therefore identified a new susceptibility locus for HPS. Patients with hamartomatous polyposis in the colon associated with ganglioneuromatosis should be referred for genetic assessments.

Keywords: Colorectal Cancer; Ganglioneuromas; Hamartomatous Polyps; SMAD Signaling.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Colonic Polyps / diagnosis
  • Colonic Polyps / enzymology
  • Colonic Polyps / genetics*
  • DNA Mutational Analysis
  • Digestive System Neoplasms / diagnosis
  • Digestive System Neoplasms / enzymology
  • Digestive System Neoplasms / genetics*
  • Down-Regulation
  • Exome*
  • Female
  • Ganglioneuroma / diagnosis
  • Ganglioneuroma / enzymology
  • Ganglioneuroma / genetics*
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease
  • Germ-Line Mutation*
  • HEK293 Cells
  • Humans
  • Male
  • Multiple Endocrine Neoplasia Type 2b / diagnosis
  • Multiple Endocrine Neoplasia Type 2b / enzymology
  • Multiple Endocrine Neoplasia Type 2b / genetics*
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Peutz-Jeghers Syndrome / diagnosis
  • Peutz-Jeghers Syndrome / enzymology
  • Peutz-Jeghers Syndrome / genetics*
  • Phenotype
  • Smad8 Protein / genetics*
  • Smad8 Protein / metabolism
  • Transfection


  • SMAD9 protein, human
  • Smad8 Protein
  • PTEN Phosphohydrolase
  • PTEN protein, human

Supplementary concepts

  • Ganglioneuromatosis of the Alimentary Tract