ORIGINAL ARTICLES

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

S Aretz¹, D Stienen¹, S Uhlhaas¹, M Stolte², M M Entius³, S Loff⁴, W Back⁵, A Kaufmann¹, K-M Keller⁶, S H Blaas⁷, R Siebert⁸, S Vogt¹, S Spranger⁹, E Holinski-Feder¹⁰, L Sunde¹¹, P Propping¹, W Friedl¹

¹ Institute of Human Genetics, University of Bonn, Germany
² Institute of Pathology, Klinikum Bayreuth GmbH, Bayreuth, Germany
³ MRC-Holland, Amsterdam, The Netherlands
⁴ Department of Children Surgery, University Hospital Giessen and Marburg, Germany
⁵ Institute of Pathology, University Hospital Mannheim, Germany
⁶ Deutsche Klinik für Diagnostik (DKD) Wiesbaden, Germany
⁷ Department of Internal Medicine I, University of Regensburg, Germany
⁸ Institute of Human Genetics, University of Kiel, Germany
⁹ Praxis für Humangenetik, Bremen, Germany
¹⁰ Medizinisch-Genetisches Zentrum, Munich, Germany
¹¹ Department of Clinical Genetics, Aarhus University Hospital, Denmark

Dr S Aretz, Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany; stefan.aretz{at}ukb.uni-bonn.de

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.

Abbreviations: BDGP, Berkeley Drosophila Genome Project; CCS, Cronkhite–Canada syndrome; HHT, hereditary haemorrhagic telangiectasia; HMPS, hereditary mixed polyposis syndromes; JPS, juvenile polyposis syndrome; MLPA, multiplex ligation-dependent probe amplification; OMIM, Online Mendelian Inheritance in Man; RT, reverse transcriptase

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