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High proportion of large genomic deletions and genotype-phenotype update in 80 unrelated families with Juvenile Polyposis Syndrome
  1. Stefan Aretz (stefan.aretz{at}ukb.uni-bonn.de)
  1. Institute of Human Genetics, University Hospital of Bonn, Germany
    1. Dietlinde Stienen (d.stienen{at}uni-bonn.de)
    1. Institute of Human Genetics, University Hospital of Bonn, Germany
      1. Siegfreid Uhlhaas (siegfried.uhlhaas{at}ukb.uni-bonn.de)
      1. Institute of Human Genetics, University Hospital of Bonn, Germany
        1. Manfred Stolte (pathologie{at}klinikum-bayreuth.de)
        1. Institute of Pathology, Klinikum Bayreuth, Germany
          1. Mark M Entius (info{at}mlpa.com)
          1. MRC-Holland, Netherlands
            1. Steffan Loff (loff{at}med.uni-marburg.de)
            1. Department of Children Surgery, University Hospital Giessen and Marburg, Germany
              1. Walter Back (walter.back{at}path.ma.uni-heidelberg.de)
              1. Institute of Pathology, University Hospital Mannheim, Germany
                1. Astrid Kaufmann (astrid.kaufmann{at}uni-bonn.de)
                1. Institute of Human Genetics, University Hospital of Bonn, Germany
                  1. Klaus-Michael Keller (keller.paed{at}dkd-wiesbaden.de)
                  1. Deutsche Klinik für Diagnostik (DKD) Wiesbaden, Germany
                    1. Stefan H Blaas (stefan.blaas{at}klinik.uni-regensburg.de)
                    1. Department of Internal Medicine I, University of Regensburg, Germany
                      1. Reiner Siebert (rsiebert{at}medgen.uni-kiel.de)
                      1. Institute of Human Genetics, University of Kiel, Germany
                        1. Stefanie Vogt (stefanie.vogt{at}uni-bonn.de)
                        1. Institute of Human Genetics, University Hospital of Bonn, Germany
                          1. Stefanie Spranger (sspranger{at}aol.com)
                          1. Praxis für Humangenetik, Bremen, Germany
                            1. Elke Holinski-Feder (elkeholinski-feder{at}t-online.de)
                            1. Medizinisch-Genetisches Zentrum, Munich, Germany
                              1. Lone Sunde (lsund{at}as.aaa.dk)
                              1. Department of Clinical Genetics, Aarhus University Hospital, Denmark
                                1. Peter Propping (propping{at}uni-bonn.de)
                                1. Institute of Human Genetics, University Hospital of Bonn, Germany
                                  1. Waltraut Friedl (waltraut.friedl{at}ukb.uni-bonn.de)
                                  1. Institute of Human Genetics, University Hospital of Bonn, Germany

                                    Abstract

                                    Germline point mutations in the SMAD4 and BMPR1A genes have been reported in around 40% of patients with juvenile polyposis syndrome (JPS). We performed mutation analysis in 80 unrelated patients of whom 65 met the clinical criteria for JPS (typical JPS) and 15 were suspected to have JPS. By direct sequencing of the two genes we identified point mutations in 30 patients (46% of typical JPS). Using MLPA we detected large genomic SMAD4 or BMPR1A deletions in 14% of all patients with typical JPS (six deletions in SMAD4 and three deletions in BMPR1A). Thus, screening for large deletions raised the mutation detection rate to 60% in the 65 patients with typical JPS. Mutation analysis of the PTEN gene in the remaining 41 SMAD4 and BMPR1A mutation negative cases uncovered a point mutation in two patients (5%). We identified a strong genotype-phenotype correlation regarding gastric polyposis, gastric cancer, and hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) in JPS patients: SMAD4 mutation carriers had a significantly higher frequency of gastric polyposis (73%) compared to 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 gastric polyps (p<0.001). In 22% of the 23 unrelated SMAD4 mutation carriers, HHT was also diagnosed clinically. In many JPS patients with identified germline mutation, the documented histologic findings encompassed a wide distribution of different polyp types, comparable to that described in hereditary mixed polyposis syndromes (HMPS).

                                    • BMPR1A
                                    • Genomic deletions
                                    • Juvenile polyposis syndrome
                                    • MLPA
                                    • SMAD4

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