Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation and tumor characteristics
Identifieur interne : 007C40 ( Main/Exploration ); précédent : 007C39; suivant : 007C41Classifying MLH1 and MSH2 variants using bioinformatic prediction, splicing assays, segregation and tumor characteristics
Auteurs : Sven Arnold [Australie] ; Daniel D. Buchanan [Australie] ; Melissa Barker [Australie] ; Lesley Jaskowski [Australie] ; Michael D. Walsh [Australie] ; Genevieve Birney [Australie] ; Michael O. Woods [Canada] ; John L. Hopper [Australie] ; Mark A. Jenkins [Australie] ; Melissa A. Brown ; Sean V. Tavtigian [France] ; David E. Goldgar [États-Unis] ; Joanne P. Young [Australie] ; Amanda B. Spurdle [Australie]Source :
- Human mutation [ 1059-7794 ] ; 2009.
Abstract
Reliable methods for predicting functional consequences of variants in disease genes would be beneficial in the clinical setting. This study was undertaken to predict, and confirm
Url:
DOI: 10.1002/humu.20936
PubMed: 19267393
PubMed Central: 2707453
Affiliations:
- Australie, Canada, France, États-Unis
- Auvergne-Rhône-Alpes, Rhône-Alpes, Utah, Victoria (État)
- Lyon, Melbourne
- Université de Melbourne
Links toward previous steps (curation, corpus...)
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- to stream Pmc, to step Checkpoint: 002844
- to stream Ncbi, to step Merge: 000548
- to stream Ncbi, to step Curation: 000548
- to stream Ncbi, to step Checkpoint: 000548
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Le document en format XML
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and <italic>MSH2</italic>
variants using bioinformatic prediction, splicing assays, segregation and tumor characteristics</title>
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<author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name>
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<author><name sortKey="Jenkins, Mark A" sort="Jenkins, Mark A" uniqKey="Jenkins M" first="Mark A." last="Jenkins">Mark A. Jenkins</name>
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<author><name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V." last="Tavtigian">Sean V. Tavtigian</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Classifying <italic>MLH1</italic>
and <italic>MSH2</italic>
variants using bioinformatic prediction, splicing assays, segregation and tumor characteristics</title>
<author><name sortKey="Arnold, Sven" sort="Arnold, Sven" uniqKey="Arnold S" first="Sven" last="Arnold">Sven Arnold</name>
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<author><name sortKey="Buchanan, Daniel D" sort="Buchanan, Daniel D" uniqKey="Buchanan D" first="Daniel D." last="Buchanan">Daniel D. Buchanan</name>
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<author><name sortKey="Barker, Melissa" sort="Barker, Melissa" uniqKey="Barker M" first="Melissa" last="Barker">Melissa Barker</name>
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<author><name sortKey="Jaskowski, Lesley" sort="Jaskowski, Lesley" uniqKey="Jaskowski L" first="Lesley" last="Jaskowski">Lesley Jaskowski</name>
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<country xml:lang="fr">Australie</country>
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<author><name sortKey="Walsh, Michael D" sort="Walsh, Michael D" uniqKey="Walsh M" first="Michael D." last="Walsh">Michael D. Walsh</name>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane</wicri:regionArea>
<wicri:noRegion>Brisbane</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Queensland, Brisbane, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Medicine, University of Queensland, Brisbane</wicri:regionArea>
<wicri:noRegion>Brisbane</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Birney, Genevieve" sort="Birney, Genevieve" uniqKey="Birney G" first="Genevieve" last="Birney">Genevieve Birney</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane</wicri:regionArea>
<wicri:noRegion>Brisbane</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Woods, Michael O" sort="Woods, Michael O" uniqKey="Woods M" first="Michael O." last="Woods">Michael O. Woods</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL</wicri:regionArea>
<wicri:noRegion>NL</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name>
<affiliation wicri:level="4"><nlm:aff id="A4">Centre for Genetic Epidemiology, University of Melbourne, Melbourne, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Centre for Genetic Epidemiology, University of Melbourne, Melbourne</wicri:regionArea>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
<settlement type="city">Melbourne</settlement>
</placeName>
<orgName type="university">Université de Melbourne</orgName>
</affiliation>
</author>
<author><name sortKey="Jenkins, Mark A" sort="Jenkins, Mark A" uniqKey="Jenkins M" first="Mark A." last="Jenkins">Mark A. Jenkins</name>
<affiliation wicri:level="4"><nlm:aff id="A4">Centre for Genetic Epidemiology, University of Melbourne, Melbourne, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Centre for Genetic Epidemiology, University of Melbourne, Melbourne</wicri:regionArea>
<placeName><settlement type="city">Melbourne</settlement>
<region type="état">Victoria (État)</region>
<settlement type="city">Melbourne</settlement>
</placeName>
<orgName type="university">Université de Melbourne</orgName>
</affiliation>
</author>
<author><name sortKey="Brown, Melissa A" sort="Brown, Melissa A" uniqKey="Brown M" first="Melissa A." last="Brown">Melissa A. Brown</name>
<affiliation><nlm:aff id="A5">School of Medicine, and School of Molecular and Microbial Sciences, University of Queensland, Brisbane</nlm:aff>
<wicri:noCountry code="subfield">Brisbane</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Tavtigian, Sean V" sort="Tavtigian, Sean V" uniqKey="Tavtigian S" first="Sean V." last="Tavtigian">Sean V. Tavtigian</name>
<affiliation wicri:level="3"><nlm:aff id="A6">International Agency for Research on Cancer, Lyon, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>International Agency for Research on Cancer, Lyon</wicri:regionArea>
<placeName><region type="region">Auvergne-Rhône-Alpes</region>
<region type="old region">Rhône-Alpes</region>
<settlement type="city">Lyon</settlement>
</placeName>
</affiliation>
</author>
<author><name sortKey="Goldgar, David E" sort="Goldgar, David E" uniqKey="Goldgar D" first="David E." last="Goldgar">David E. Goldgar</name>
<affiliation wicri:level="2"><nlm:aff id="A7">Department of Dermatology, University of Utah, Salt Lake City, Utah, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Dermatology, University of Utah, Salt Lake City, Utah</wicri:regionArea>
<placeName><region type="state">Utah</region>
</placeName>
</affiliation>
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<author><name sortKey="Young, Joanne P" sort="Young, Joanne P" uniqKey="Young J" first="Joanne P." last="Young">Joanne P. Young</name>
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<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane</wicri:regionArea>
<wicri:noRegion>Brisbane</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Queensland, Brisbane, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Medicine, University of Queensland, Brisbane</wicri:regionArea>
<wicri:noRegion>Brisbane</wicri:noRegion>
</affiliation>
</author>
<author><name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B." last="Spurdle">Amanda B. Spurdle</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane</wicri:regionArea>
<wicri:noRegion>Brisbane</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">School of Medicine, University of Queensland, Brisbane, Australia</nlm:aff>
<country xml:lang="fr">Australie</country>
<wicri:regionArea>School of Medicine, University of Queensland, Brisbane</wicri:regionArea>
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</analytic>
<series><title level="j">Human mutation</title>
<idno type="ISSN">1059-7794</idno>
<idno type="eISSN">1098-1004</idno>
<imprint><date when="2009">2009</date>
</imprint>
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<front><div type="abstract" xml:lang="en"><p id="P1">Reliable methods for predicting functional consequences of variants in disease genes would be beneficial in the clinical setting. This study was undertaken to predict, and confirm <italic>in vitro</italic>
, splicing aberrations associated with mismatch repair (MMR) variants identified in familial colon cancer patients. Six programs were used to predict the effect of 13 <italic>MLH1</italic>
and 6 <italic>MSH2</italic>
gene variants on pre-mRNA splicing. mRNA from cycloheximide-treated lymphoblastoid cell lines of variant carriers was screened for splicing aberrations. Tumors of variant carriers were tested for microsatellite instability and MMR protein expression. Variant segregation in families was assessed using Bayes factor causality analysis. Amino acid alterations were examined for evolutionary conservation and physicochemical properties. Splicing aberrations were detected for ten variants, including a frameshift as a minor cDNA product, and altered ratio of known alternate splice products. Loss of splice sites was well predicted by splice site prediction programs SpliceSiteFinder (90%) and NNSPLICE (90%), but consequence of splice site loss was less accurately predicted. No aberrations correlated with ESE predictions for the nine exonic variants studied. Seven of eight missense variants had normal splicing (88%), but only one was a substitution considered neutral from evolutionary/physicochemical analysis. Combined with information from tumor and segregation analysis, and literature review, 16/19 variants were considered clinically relevant. Bioinformatic tools for prediction of splicing aberrations need improvement before use without supporting studies to assess variant pathogenicity. Classification of mismatch repair gene variants is assisted by a comprehensive approach which includes <italic>in vitro</italic>
, tumor pathology, clinical, and evolutionary conservation data.</p>
</div>
</front>
</TEI>
<affiliations><list><country><li>Australie</li>
<li>Canada</li>
<li>France</li>
<li>États-Unis</li>
</country>
<region><li>Auvergne-Rhône-Alpes</li>
<li>Rhône-Alpes</li>
<li>Utah</li>
<li>Victoria (État)</li>
</region>
<settlement><li>Lyon</li>
<li>Melbourne</li>
</settlement>
<orgName><li>Université de Melbourne</li>
</orgName>
</list>
<tree><noCountry><name sortKey="Brown, Melissa A" sort="Brown, Melissa A" uniqKey="Brown M" first="Melissa A." last="Brown">Melissa A. Brown</name>
</noCountry>
<country name="Australie"><noRegion><name sortKey="Arnold, Sven" sort="Arnold, Sven" uniqKey="Arnold S" first="Sven" last="Arnold">Sven Arnold</name>
</noRegion>
<name sortKey="Barker, Melissa" sort="Barker, Melissa" uniqKey="Barker M" first="Melissa" last="Barker">Melissa Barker</name>
<name sortKey="Birney, Genevieve" sort="Birney, Genevieve" uniqKey="Birney G" first="Genevieve" last="Birney">Genevieve Birney</name>
<name sortKey="Buchanan, Daniel D" sort="Buchanan, Daniel D" uniqKey="Buchanan D" first="Daniel D." last="Buchanan">Daniel D. Buchanan</name>
<name sortKey="Buchanan, Daniel D" sort="Buchanan, Daniel D" uniqKey="Buchanan D" first="Daniel D." last="Buchanan">Daniel D. Buchanan</name>
<name sortKey="Hopper, John L" sort="Hopper, John L" uniqKey="Hopper J" first="John L." last="Hopper">John L. Hopper</name>
<name sortKey="Jaskowski, Lesley" sort="Jaskowski, Lesley" uniqKey="Jaskowski L" first="Lesley" last="Jaskowski">Lesley Jaskowski</name>
<name sortKey="Jenkins, Mark A" sort="Jenkins, Mark A" uniqKey="Jenkins M" first="Mark A." last="Jenkins">Mark A. Jenkins</name>
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<name sortKey="Spurdle, Amanda B" sort="Spurdle, Amanda B" uniqKey="Spurdle A" first="Amanda B." last="Spurdle">Amanda B. Spurdle</name>
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