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The identification of germline variants predisposing to hereditary nonpolyposis colorectal cancer (HNPCC) is crucial for clinical management of carriers, but several probands remain negative for such variants or bear variants of uncertain significance (VUS). Here we describe the results of integrative molecular analyses in 132 HNPCC patients providing evidences for improved genetic testing of HNPCC with traditional or next generation methods. Patients were screened for: germline allele-specific expression (ASE), nucleotide variants, rearrangements and promoter methylation of mismatch repair (MMR) genes; germline EPCAM rearrangements; tumor microsatellite instability (MSI) and immunohistochemical (IHC) MMR protein expression. Probands negative for pathogenic variants of MMR genes were screened for germline APC and MUTYH sequence variants. Most germline defects identified were sequence variants and rearrangements of MMR genes. Remarkably, altered germline ASE of MMR genes was detected in 8/22 (36.5%) probands analyzed, including 3 cases negative at other screenings. Moreover, ASE provided evidence for the pathogenic role and guided the characterization of a VUS shared by 2 additional probands. No germline MMR gene promoter methylation was observed and only one EPCAM rearrangement was detected. In several cases, tumor IHC and MSI diverged from germline screening results. Notably, APC or biallelic MUTYH germline defects were identified in 2/19 probands negative for pathogenic variants of MMR genes. Our results show that ASE complements gDNA-based analyses in the identification of MMR defects and in the characterization of VUS affecting gene expression, increasing the number of germline alterations detected. An appreciable fraction of probands negative for MMR gene variants harbors APC or MUTYH variants. These results indicate that germline ASE analysis and screening for APC and MUTYH defects should be included in HNPCC diagnostic algorithms.
Pubmed ID: 24278394 RIS Download
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IDbases are locus-specific databases for immunodeficiency-causing mutations. Our aim is to establish database for every immunodeficiency or provide links to those maintained elsewhere. IDbases contain in addition to gene mutation, also information about clinical presentation. Information has been collected from literature as well as received directly from researchers. It would be most glad if those analyzing mutations would send their information by using the interactive web submission available in each database. A number of articles have been published related to IDbases. IDbases are curated and distributed with proprietary MUTbase software suite.
View all literature mentionsEvaluates disease-causing potential of sequence alterations.
View all literature mentionsData analysis service to predict whether an amino acid substitution affects protein function based on sequence homology and the physical properties of amino acids. SIFT can be applied to naturally occurring nonsynonymous polymorphisms and laboratory-induced missense mutations. (entry from Genetic Analysis Software) Web service is also available.
View all literature mentionsDatabase on the sequence of the euchromatic genome of Drosophila melanogaster In addition to genomic sequencing, the BDGP is 1) producing gene disruptions using P element-mediated mutagenesis on a scale unprecedented in metazoans; 2) characterizing the sequence and expression of cDNAs; and 3) developing informatics tools that support the experimental process, identify features of DNA sequence, and allow us to present up-to-date information about the annotated sequence to the research community. Resources * Universal Proteomics Resource: Search for clones for expression and tissue culture * Materials: Request genomic or cDNA clones, library filters or fly stocks * Download Sequence data sets and annotations in fasta or xml format by http or ftp * Publications: Browse or download BDGP papers * Methods: BDGP laboratory protocols and vector maps * Analysis Tools: Search sequences for CRMs, promoters, splice sites, and gene predictions * Apollo: Genome annotation viewer and editor September 15, 2009 Illumina RNA-Seq data from 30 developmental time points of D. melanogaster has been submitted to the Short Read Archive at NCBI as part of the modENCODE project. The data set currently contains 2.2 billion single-end and paired reads and over 201 billion base pairs.
View all literature mentionsSoftware tool which predicts possible impact of amino acid substitution on structure and function of human protein using straightforward physical and comparative considerations. PolyPhen-2 is new development of PolyPhen tool for annotating coding nonsynonymous SNPs.
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