ENG mutations in MADH4/BMPR1A mutation negative patients with juvenile polyposis

Department of Preventive Medicine, Creighton University, Omaha, Nebraska, United States
Clinical Genetics (Impact Factor: 3.65). 02/2007; 71(1):91-2. DOI: 10.1111/j.1399-0004.2007.00734.x
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    ABSTRACT: Familial adenomatous polyposis has been the first form of inherited intestinal polyposis to be recognized. For a long time it has been considered the main polyposis syndrome, associated with an easily recognizable phenotype, with a marginal role attributed to a few very rare hamartomatous conditions. More recently, it has been gradually demonstrated that the intestinal polyposes encompass a range of conditions within a wide spectrum of disease severity, polyp histology, and extraintestinal manifestations. A growing number of genes and phenotypes has been identified, and heterogeneity of somatic molecular pathways underlying epithelial transformation in different syndromes and associated tumors has been documented. Increasing knowledge on the molecular bases and more widespread use of genetic tests has shown phenotypic overlaps between conditions that were previously considered distinct, highlighting diagnostic difficulties. With the advent of next generation sequencing, the diagnosis and the classification of these syndromes will be progressively based more on genetic testing results. However, the phenotypic variability documented among patients with mutations in the same genes cannot be fully explained by different expressivity, indicating a role for as yet unknown modifying factors. Until the latter will be identified, the management of patients with polyposis syndromes should be guided by both clinical and genetic findings. © 2013 Wiley Periodicals, Inc.
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    ABSTRACT: Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterised by multiple gastrointestinal juvenile polyps and an increased risk of colorectal cancer. This syndrome is caused by germline mutation of either SMAD4 or BMPR1A, and possibly ENG. PTEN, originally linked to Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, has also been associated with JPS. By direct sequencing, germline mutations are found in only 30-40% of patients with a JPS phenotype. Therefore, alternative ways of inactivation of the known JPS genes, or additional genes predisposing to JPS may be involved. In this study, a comprehensive genetic analysis of SMAD4, BMPR1A, PTEN and ENG is performed through direct sequencing and multiplex ligation-dependent probe amplification (MLPA) in JPS patients. Archival material of 29 patients with JPS from 27 families was collected. Direct sequencing and MLPA analysis were performed to search for germline defects in SMAD4, BMPR1A, PTEN and ENG. A germline defect in SMAD4, BMPR1A or PTEN was found in 13 of 27 (48.1%) unrelated JPS patients. Nine mutations (33.3%) were detected by direct sequencing, including six (22.2%) SMAD4 mutations and three (11.1%) BMPR1A mutations. MLPA identified four additional patients (14.8%) with germline hemizygous large genomic deletions, including one deletion of SMAD4, one deletion of exons 10 and 11 of BMPR1A, and two unrelated patients with deletion of both BMPR1A and PTEN. No ENG gene mutations were found. Large genomic deletions of SMAD4, BMPR1A and PTEN are a common cause of JPS. Using direct sequencing and MLPA, a germline defect was detected in 48.1% of JPS patients. MLPA identified 14.8% (4/27) of these mutations. Since a substantial percentage of JPS patients carry a germline deletion and MLPA is a reliable and user-friendly technique, it is concluded that MLPA is a valuable adjunct in JPS diagnosis.
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