J Med Genet 44:702-709 doi:10.1136/jmg.2007.052506
  • Original article

High proportion of large genomic deletions and a genotype–phenotype update in 80 unrelated families with juvenile polyposis syndrome

  1. S Aretz1,
  2. D Stienen1,
  3. S Uhlhaas1,
  4. M Stolte2,
  5. M M Entius3,
  6. S Loff4,
  7. W Back5,
  8. A Kaufmann1,
  9. K-M Keller6,
  10. S H Blaas7,
  11. R Siebert8,
  12. S Vogt1,
  13. S Spranger9,
  14. E Holinski-Feder10,
  15. L Sunde11,
  16. P Propping1,
  17. W Friedl1
  1. 1
    Institute of Human Genetics, University of Bonn, Germany
  2. 2
    Institute of Pathology, Klinikum Bayreuth GmbH, Bayreuth, Germany
  3. 3
    MRC-Holland, Amsterdam, The Netherlands
  4. 4
    Department of Children Surgery, University Hospital Giessen and Marburg, Germany
  5. 5
    Institute of Pathology, University Hospital Mannheim, Germany
  6. 6
    Deutsche Klinik für Diagnostik (DKD) Wiesbaden, Germany
  7. 7
    Department of Internal Medicine I, University of Regensburg, Germany
  8. 8
    Institute of Human Genetics, University of Kiel, Germany
  9. 9
    Praxis für Humangenetik, Bremen, Germany
  10. 10
    Medizinisch-Genetisches Zentrum, Munich, Germany
  11. 11
    Department of Clinical Genetics, Aarhus University Hospital, Denmark
  1. Dr S Aretz, Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany; stefan.aretz{at}
  • Received 22 June 2007
  • Revised 14 August 2007
  • Accepted 16 August 2007
  • Published Online First 14 September 2007


Background: In patients with juvenile polyposis syndrome (JPS) the frequency of large genomic deletions in the SMAD4 and BMPR1A genes was unknown.

Methods: Mutation and phenotype analysis was used in 80 unrelated patients of whom 65 met the clinical criteria for JPS (typical JPS) and 15 were suspected to have JPS.

Results: By direct sequencing of the two genes, point mutations were identified in 30 patients (46% of typical JPS). Using MLPA, large genomic deletions were found in 14% of all patients with typical JPS (six deletions in SMAD4 and three deletions in BMPR1A). Mutation analysis of the PTEN gene in the remaining 41 mutation negative cases uncovered a point mutation in two patients (5%). SMAD4 mutation carriers had a significantly higher frequency of gastric polyposis (73%) than did patients with BMPR1A mutations (8%) (p<0.001); all seven cases of gastric cancer occurred in families with SMAD4 mutations. SMAD4 mutation carriers with gastric polyps were significantly older at gastroscopy than those without (p<0.001). In 22% of the 23 unrelated SMAD4 mutation carriers, hereditary hemorrhagic telangiectasia (HHT) was also diagnosed clinically. The documented histologic findings encompassed a wide distribution of different polyp types, comparable with that described in hereditary mixed polyposis syndromes (HMPS).

Conclusions: Screening for large deletions raised the mutation detection rate to 60% in the 65 patients with typical JPS. A strong genotype-phenotype correlation for gastric polyposis, gastric cancer, and HHT was identified, which should have implications for counselling and surveillance. Histopathological results in hamartomatous polyposis syndromes must be critically interpreted.


  • Competing interests: None declared.

  • Abbreviations:
    Berkeley Drosophila Genome Project
    Cronkhite–Canada syndrome
    hereditary haemorrhagic telangiectasia
    hereditary mixed polyposis syndromes
    juvenile polyposis syndrome
    multiplex ligation-dependent probe amplification
    Online Mendelian Inheritance in Man
    reverse transcriptase