Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation‐dependent probe amplification
Identifieur interne : 002902 ( Main/Corpus ); précédent : 002901; suivant : 002903Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation‐dependent probe amplification
Auteurs : Ana Djarmati ; Miodrag Gužvi ; Anne Grünewald ; Anthony E. Lang ; Peter P. Pramstaller ; David K. Simon ; Angela M. Kaindl ; Peter Vieregge ; Anders O. H. Nygren ; Christian Beetz ; Katja Hedrich ; Christine KleinSource :
- Movement Disorders [ 0885-3185 ] ; 2007-09-15.
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- KwdEn :
Abstract
Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa‐responsive dystonia (DRD), and myoclonus‐dystonia (M‐D) should include screening for small sequence changes and for large exonic rearrangements in disease‐associated genes. In diagnostic and research settings, the latter is frequently omitted or performed by laborious and expensive quantitative real‐time PCR (qPCR). Our study aimed to evaluate the utility of a novel method, multiplex ligation‐dependent probe amplification (MLPA), in molecular diagnostics of movement disorders. We have analyzed, by MLPA, genomic DNA from 21 patients affected with PD, DRD, or M‐D, in which the presence of exon rearrangement(s) (n = 20) or of a specific point mutation (detectable by MLPA, n = 1) had been established previously by qPCR or sequencing. In parallel, we have studied, in a blinded fashion, DNA from 49 patients with an unknown mutational status. Exon rearrangements were evident in 20 samples with previously established mutations; in the 21st sample the known specific point mutation was detected. We conclude that MLPA represents a reliable method for large‐scale and cost‐effective gene dosage screening of various movement disorders genes. This finding reaches far beyond a simple technical advancement and has two major implications: (1) By improving the availability of comprehensive genetic testing, it supports clinicians in the establishment of a genetically defined diagnosis; (2) By enabling gene dosage testing of several genes simultaneously, it significantly facilitates the mutational analysis of large patient and control populations and thereby constitutes the prerequisite for meaningful phenotype–genotype correlations. © 2007 Movement Disorder Society
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DOI: 10.1002/mds.21370
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation‐dependent probe amplification</title><author><name sortKey="Djarmati, Ana" sort="Djarmati, Ana" uniqKey="Djarmati A" first="Ana" last="Djarmati">Ana Djarmati</name><affiliation><mods:affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Guzvi, Miodrag" sort="Guzvi, Miodrag" uniqKey="Guzvi M" first="Miodrag" last="Gužvi">Miodrag Gužvi</name><affiliation><mods:affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences “Vinča”, Belgrade, Serbia</mods:affiliation></affiliation><affiliation><mods:affiliation>Current Address: Institute for Immunology, Ludwig‐Maximilian's University, Munich, Germany</mods:affiliation></affiliation></author><author><name sortKey="Grunewald, Anne" sort="Grunewald, Anne" uniqKey="Grunewald A" first="Anne" last="Grünewald">Anne Grünewald</name><affiliation><mods:affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Lang, Anthony E" sort="Lang, Anthony E" uniqKey="Lang A" first="Anthony E." last="Lang">Anthony E. 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Lang</name><affiliation><mods:affiliation>Movement Disorders Centre, Toronto Western Hospital, Toronto, Canada</mods:affiliation></affiliation></author><author><name sortKey="Pramstaller, Peter P" sort="Pramstaller, Peter P" uniqKey="Pramstaller P" first="Peter P." last="Pramstaller">Peter P. Pramstaller</name><affiliation><mods:affiliation>Institute of Genetic Medicine, EURAC‐Research, Bolzano‐Bozen, Italy</mods:affiliation></affiliation></author><author><name sortKey="Simon, David K" sort="Simon, David K" uniqKey="Simon D" first="David K." last="Simon">David K. Simon</name><affiliation><mods:affiliation>Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA</mods:affiliation></affiliation></author><author><name sortKey="Kaindl, Angela M" sort="Kaindl, Angela M" uniqKey="Kaindl A" first="Angela M." last="Kaindl">Angela M. Kaindl</name><affiliation><mods:affiliation>Department of Pediatric Neurology, Charité University Medicine Berlin, Berlin, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Pediatric Neurology, University Hospital Dresden, Dresden, Germany</mods:affiliation></affiliation></author><author><name sortKey="Vieregge, Peter" sort="Vieregge, Peter" uniqKey="Vieregge P" first="Peter" last="Vieregge">Peter Vieregge</name><affiliation><mods:affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Neurology, Hospital Lippe‐Lemgo, Lemgo, Germany</mods:affiliation></affiliation></author><author><name sortKey="Nygren, Anders O H" sort="Nygren, Anders O H" uniqKey="Nygren A" first="Anders O. H." last="Nygren">Anders O. H. Nygren</name><affiliation><mods:affiliation>MRC‐Holland, Amsterdam, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Beetz, Christian" sort="Beetz, Christian" uniqKey="Beetz C" first="Christian" last="Beetz">Christian Beetz</name><affiliation><mods:affiliation>Institut of Clinical Chemistry and Laboratory Diagnostics, University Hospital of the Friedrich Schiller University, Jena, Germany</mods:affiliation></affiliation></author><author><name sortKey="Hedrich, Katja" sort="Hedrich, Katja" uniqKey="Hedrich K" first="Katja" last="Hedrich">Katja Hedrich</name><affiliation><mods:affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation></author><author><name sortKey="Klein, Christine" sort="Klein, Christine" uniqKey="Klein C" first="Christine" last="Klein">Christine Klein</name><affiliation><mods:affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Movement Disorders</title><title level="j" type="sub">Official Journal of the Movement Disorder Society</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="ISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2007-09-15">2007-09-15</date><biblScope unit="volume">22</biblScope><biblScope unit="issue">12</biblScope><biblScope unit="page" from="1708">1708</biblScope><biblScope unit="page" to="1714">1714</biblScope></imprint><idno type="ISSN">0885-3185</idno></series><idno type="istex">171DF0EB23EB4E4906DA047399227B3480C5F7BB</idno><idno type="DOI">10.1002/mds.21370</idno><idno type="ArticleID">MDS21370</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0885-3185</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Parkinson's disease</term><term>dopa‐responsive dystonia</term><term>exon rearrangements</term><term>multiplex ligation‐dependent probe amplification</term><term>myoclonus‐dystonia</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa‐responsive dystonia (DRD), and myoclonus‐dystonia (M‐D) should include screening for small sequence changes and for large exonic rearrangements in disease‐associated genes. In diagnostic and research settings, the latter is frequently omitted or performed by laborious and expensive quantitative real‐time PCR (qPCR). Our study aimed to evaluate the utility of a novel method, multiplex ligation‐dependent probe amplification (MLPA), in molecular diagnostics of movement disorders. We have analyzed, by MLPA, genomic DNA from 21 patients affected with PD, DRD, or M‐D, in which the presence of exon rearrangement(s) (n = 20) or of a specific point mutation (detectable by MLPA, n = 1) had been established previously by qPCR or sequencing. In parallel, we have studied, in a blinded fashion, DNA from 49 patients with an unknown mutational status. Exon rearrangements were evident in 20 samples with previously established mutations; in the 21st sample the known specific point mutation was detected. We conclude that MLPA represents a reliable method for large‐scale and cost‐effective gene dosage screening of various movement disorders genes. This finding reaches far beyond a simple technical advancement and has two major implications: (1) By improving the availability of comprehensive genetic testing, it supports clinicians in the establishment of a genetically defined diagnosis; (2) By enabling gene dosage testing of several genes simultaneously, it significantly facilitates the mutational analysis of large patient and control populations and thereby constitutes the prerequisite for meaningful phenotype–genotype correlations. © 2007 Movement Disorder Society</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Ana Djarmati PhD</name><affiliations><json:string>Department of Neurology, University of Lübeck, Lübeck, Germany</json:string><json:string>Department of Human Genetics, University of Lübeck, Lübeck, Germany</json:string></affiliations></json:item><json:item><name>Miodrag Gužvić MSc</name><affiliations><json:string>Department of Neurology, University of Lübeck, Lübeck, Germany</json:string><json:string>Department of Human Genetics, University of Lübeck, Lübeck, Germany</json:string><json:string>Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences “Vinča”, Belgrade, Serbia</json:string><json:string>Current Address: Institute for Immunology, Ludwig‐Maximilian's University, Munich, Germany</json:string></affiliations></json:item><json:item><name>Anne Grünewald MSc</name><affiliations><json:string>Department of Neurology, University of Lübeck, Lübeck, Germany</json:string><json:string>Department of Human Genetics, University of Lübeck, Lübeck, Germany</json:string></affiliations></json:item><json:item><name>Anthony E. Lang MD</name><affiliations><json:string>Movement Disorders Centre, Toronto Western Hospital, Toronto, Canada</json:string></affiliations></json:item><json:item><name>Peter P. Pramstaller MD</name><affiliations><json:string>Institute of Genetic Medicine, EURAC‐Research, Bolzano‐Bozen, Italy</json:string></affiliations></json:item><json:item><name>David K. Simon MD, PhD</name><affiliations><json:string>Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA</json:string></affiliations></json:item><json:item><name>Angela M. Kaindl MD</name><affiliations><json:string>Department of Pediatric Neurology, Charité University Medicine Berlin, Berlin, Germany</json:string><json:string>Department of Pediatric Neurology, University Hospital Dresden, Dresden, Germany</json:string></affiliations></json:item><json:item><name>Peter Vieregge MD</name><affiliations><json:string>Department of Neurology, University of Lübeck, Lübeck, Germany</json:string><json:string>Department of Neurology, Hospital Lippe‐Lemgo, Lemgo, Germany</json:string></affiliations></json:item><json:item><name>Anders O. H. Nygren PhD</name><affiliations><json:string>MRC‐Holland, Amsterdam, The Netherlands</json:string></affiliations></json:item><json:item><name>Christian Beetz PhD</name><affiliations><json:string>Institut of Clinical Chemistry and Laboratory Diagnostics, University Hospital of the Friedrich Schiller University, Jena, Germany</json:string></affiliations></json:item><json:item><name>Katja Hedrich PhD</name><affiliations><json:string>Department of Neurology, University of Lübeck, Lübeck, Germany</json:string><json:string>Department of Human Genetics, University of Lübeck, Lübeck, Germany</json:string></affiliations></json:item><json:item><name>Christine Klein MD</name><affiliations><json:string>Department of Neurology, University of Lübeck, Lübeck, Germany</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>multiplex ligation‐dependent probe amplification</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Parkinson's disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>dopa‐responsive dystonia</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>myoclonus‐dystonia</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>exon rearrangements</value></json:item></subject><articleId><json:string>MDS21370</json:string></articleId><language><json:string>eng</json:string></language><abstract>Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa‐responsive dystonia (DRD), and myoclonus‐dystonia (M‐D) should include screening for small sequence changes and for large exonic rearrangements in disease‐associated genes. In diagnostic and research settings, the latter is frequently omitted or performed by laborious and expensive quantitative real‐time PCR (qPCR). Our study aimed to evaluate the utility of a novel method, multiplex ligation‐dependent probe amplification (MLPA), in molecular diagnostics of movement disorders. We have analyzed, by MLPA, genomic DNA from 21 patients affected with PD, DRD, or M‐D, in which the presence of exon rearrangement(s) (n = 20) or of a specific point mutation (detectable by MLPA, n = 1) had been established previously by qPCR or sequencing. In parallel, we have studied, in a blinded fashion, DNA from 49 patients with an unknown mutational status. Exon rearrangements were evident in 20 samples with previously established mutations; in the 21st sample the known specific point mutation was detected. We conclude that MLPA represents a reliable method for large‐scale and cost‐effective gene dosage screening of various movement disorders genes. This finding reaches far beyond a simple technical advancement and has two major implications: (1) By improving the availability of comprehensive genetic testing, it supports clinicians in the establishment of a genetically defined diagnosis; (2) By enabling gene dosage testing of several genes simultaneously, it significantly facilitates the mutational analysis of large patient and control populations and thereby constitutes the prerequisite for meaningful phenotype–genotype correlations. © 2007 Movement Disorder Society</abstract><qualityIndicators><score>6.219</score><pdfVersion>1.3</pdfVersion><pdfPageSize>594 x 792 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>5</keywordCount><abstractCharCount>1797</abstractCharCount><pdfWordCount>3219</pdfWordCount><pdfCharCount>22751</pdfCharCount><pdfPageCount>7</pdfPageCount><abstractWordCount>255</abstractWordCount></qualityIndicators><title>Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation‐dependent probe amplification</title><genre><json:string>article</json:string></genre><host><volume>22</volume><publisherId><json:string>MDS</json:string></publisherId><pages><total>7</total><last>1714</last><first>1708</first></pages><issn><json:string>0885-3185</json:string></issn><issue>12</issue><subject><json:item><value>Research Article</value></json:item></subject><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1531-8257</json:string></eissn><title>Movement Disorders</title><doi><json:string>10.1002/(ISSN)1531-8257</json:string></doi></host><publicationDate>2007</publicationDate><copyrightDate>2007</copyrightDate><doi><json:string>10.1002/mds.21370</json:string></doi><id>171DF0EB23EB4E4906DA047399227B3480C5F7BB</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/171DF0EB23EB4E4906DA047399227B3480C5F7BB/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/171DF0EB23EB4E4906DA047399227B3480C5F7BB/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/171DF0EB23EB4E4906DA047399227B3480C5F7BB/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation‐dependent probe amplification</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>WILEY</p></availability><date>2007</date></publicationStmt><notesStmt><note>Deutsche Forschungsgemeinschaft - No. 436 JUG 17/2/05;</note><note>Volkswagen Foundation</note><note>University of Lübeck</note><note>German Ministry of Education and Research - No. MDNET 01GM0302;</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation‐dependent probe amplification</title><author><persName><forename type="first">Ana</forename><surname>Djarmati</surname></persName><roleName type="degree">PhD</roleName><note type="biography">The first two authors contributed equally to this study.</note><affiliation>The first two authors contributed equally to this study.</affiliation><affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation></author><author><persName><forename type="first">Miodrag</forename><surname>Gužvić</surname></persName><roleName type="degree">MSc</roleName><note type="biography">The first two authors contributed equally to this study.</note><affiliation>The first two authors contributed equally to this study.</affiliation><affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences “Vinča”, Belgrade, Serbia</affiliation><affiliation>Current Address: Institute for Immunology, Ludwig‐Maximilian's University, Munich, Germany</affiliation></author><author><persName><forename type="first">Anne</forename><surname>Grünewald</surname></persName><roleName type="degree">MSc</roleName><affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation></author><author><persName><forename type="first">Anthony E.</forename><surname>Lang</surname></persName><roleName type="degree">MD</roleName><affiliation>Movement Disorders Centre, Toronto Western Hospital, Toronto, Canada</affiliation></author><author><persName><forename type="first">Peter P.</forename><surname>Pramstaller</surname></persName><roleName type="degree">MD</roleName><affiliation>Institute of Genetic Medicine, EURAC‐Research, Bolzano‐Bozen, Italy</affiliation></author><author><persName><forename type="first">David K.</forename><surname>Simon</surname></persName><roleName type="degree">MD, PhD</roleName><affiliation>Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA</affiliation></author><author><persName><forename type="first">Angela M.</forename><surname>Kaindl</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Pediatric Neurology, Charité University Medicine Berlin, Berlin, Germany</affiliation><affiliation>Department of Pediatric Neurology, University Hospital Dresden, Dresden, Germany</affiliation></author><author><persName><forename type="first">Peter</forename><surname>Vieregge</surname></persName><roleName type="degree">MD</roleName><affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Department of Neurology, Hospital Lippe‐Lemgo, Lemgo, Germany</affiliation></author><author><persName><forename type="first">Anders O. H.</forename><surname>Nygren</surname></persName><roleName type="degree">PhD</roleName><affiliation>MRC‐Holland, Amsterdam, The Netherlands</affiliation></author><author><persName><forename type="first">Christian</forename><surname>Beetz</surname></persName><roleName type="degree">PhD</roleName><affiliation>Institut of Clinical Chemistry and Laboratory Diagnostics, University Hospital of the Friedrich Schiller University, Jena, Germany</affiliation></author><author><persName><forename type="first">Katja</forename><surname>Hedrich</surname></persName><roleName type="degree">PhD</roleName><affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation></author><author><persName><forename type="first">Christine</forename><surname>Klein</surname></persName><roleName type="degree">MD</roleName><note type="correspondence"><p>Correspondence: Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany</p></note><affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</affiliation></author></analytic><monogr><title level="j">Movement Disorders</title><title level="j" type="sub">Official Journal of the Movement Disorder Society</title><title level="j" type="abbrev">Mov. Disord.</title><idno type="pISSN">0885-3185</idno><idno type="eISSN">1531-8257</idno><idno type="DOI">10.1002/(ISSN)1531-8257</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2007-09-15"></date><biblScope unit="volume">22</biblScope><biblScope unit="issue">12</biblScope><biblScope unit="page" from="1708">1708</biblScope><biblScope unit="page" to="1714">1714</biblScope></imprint></monogr><idno type="istex">171DF0EB23EB4E4906DA047399227B3480C5F7BB</idno><idno type="DOI">10.1002/mds.21370</idno><idno type="ArticleID">MDS21370</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2007</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa‐responsive dystonia (DRD), and myoclonus‐dystonia (M‐D) should include screening for small sequence changes and for large exonic rearrangements in disease‐associated genes. In diagnostic and research settings, the latter is frequently omitted or performed by laborious and expensive quantitative real‐time PCR (qPCR). Our study aimed to evaluate the utility of a novel method, multiplex ligation‐dependent probe amplification (MLPA), in molecular diagnostics of movement disorders. We have analyzed, by MLPA, genomic DNA from 21 patients affected with PD, DRD, or M‐D, in which the presence of exon rearrangement(s) (n = 20) or of a specific point mutation (detectable by MLPA, n = 1) had been established previously by qPCR or sequencing. In parallel, we have studied, in a blinded fashion, DNA from 49 patients with an unknown mutational status. Exon rearrangements were evident in 20 samples with previously established mutations; in the 21st sample the known specific point mutation was detected. We conclude that MLPA represents a reliable method for large‐scale and cost‐effective gene dosage screening of various movement disorders genes. This finding reaches far beyond a simple technical advancement and has two major implications: (1) By improving the availability of comprehensive genetic testing, it supports clinicians in the establishment of a genetically defined diagnosis; (2) By enabling gene dosage testing of several genes simultaneously, it significantly facilitates the mutational analysis of large patient and control populations and thereby constitutes the prerequisite for meaningful phenotype–genotype correlations. © 2007 Movement Disorder Society</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>multiplex ligation‐dependent probe amplification</term></item><item><term>Parkinson's disease</term></item><item><term>dopa‐responsive dystonia</term></item><item><term>myoclonus‐dystonia</term></item><item><term>exon rearrangements</term></item></list></keywords></textClass><textClass><keywords scheme="Journal Subject"><list><head>article category</head><item><term>Research Article</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2006-10-23">Received</change><change when="2006-11-19">Registration</change><change when="2007-09-15">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/171DF0EB23EB4E4906DA047399227B3480C5F7BB/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Wiley Subscription Services, Inc., A Wiley Company</publisherName><publisherLoc>Hoboken</publisherLoc></publisherInfo><doi registered="yes">10.1002/(ISSN)1531-8257</doi><issn type="print">0885-3185</issn><issn type="electronic">1531-8257</issn><idGroup><id type="product" value="MDS"></id></idGroup><titleGroup><title type="main" xml:lang="en" sort="MOVEMENT DISORDERS">Movement Disorders</title><title type="subtitle">Official Journal of the Movement Disorder Society</title><title type="short">Mov. Disord.</title></titleGroup></publicationMeta><publicationMeta level="part" position="120"><doi origin="wiley" registered="yes">10.1002/mds.v22:12</doi><numberingGroup><numbering type="journalVolume" number="22">22</numbering><numbering type="journalIssue">12</numbering></numberingGroup><coverDate startDate="2007-09-15">15 September 2007</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="30" status="forIssue"><doi origin="wiley" registered="yes">10.1002/mds.21370</doi><idGroup><id type="unit" value="MDS21370"></id></idGroup><countGroup><count type="pageTotal" number="7"></count></countGroup><titleGroup><title type="articleCategory">Research Article</title><title type="tocHeading1">Research Articles</title></titleGroup><copyright ownership="thirdParty">Copyright © 2007 Movement Disorder Society</copyright><eventGroup><event type="manuscriptReceived" date="2006-10-23"></event><event type="manuscriptRevised" date="2006-10-23"></event><event type="manuscriptAccepted" date="2006-11-19"></event><event type="publishedOnlineEarlyUnpaginated" date="2007-08-02"></event><event type="firstOnline" date="2007-08-02"></event><event type="publishedOnlineFinalForm" date="2007-09-21"></event><event type="xmlConverted" agent="Converter:JWSART34_TO_WML3G version:2.3.2 mode:FullText source:FullText result:FullText" date="2010-03-09"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-02-02"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-31"></event></eventGroup><numberingGroup><numbering type="pageFirst">1708</numbering><numbering type="pageLast">1714</numbering></numberingGroup><correspondenceTo>Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:MDS.MDS21370.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="2"></count><count type="tableTotal" number="2"></count><count type="referenceTotal" number="20"></count><count type="wordTotal" number="4262"></count></countGroup><titleGroup><title type="main" xml:lang="en">Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation‐dependent probe amplification</title><title type="short" xml:lang="en">MLPA in the Diagnostics of Movement Disorders</title></titleGroup><creators><creator xml:id="au1" creatorRole="author" affiliationRef="#af1 #af2" noteRef="#fn1"><personName><givenNames>Ana</givenNames><familyName>Djarmati</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au2" creatorRole="author" affiliationRef="#af1 #af2 #af3" currentRef="#curr1" noteRef="#fn1"><personName><givenNames>Miodrag</givenNames><familyName>Gužvić</familyName><degrees>MSc</degrees></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Anne</givenNames><familyName>Grünewald</familyName><degrees>MSc</degrees></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af4"><personName><givenNames>Anthony E.</givenNames><familyName>Lang</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af5"><personName><givenNames>Peter P.</givenNames><familyName>Pramstaller</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af6"><personName><givenNames>David K.</givenNames><familyName>Simon</familyName><degrees>MD, PhD</degrees></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af7 #af8"><personName><givenNames>Angela M.</givenNames><familyName>Kaindl</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af1 #af9"><personName><givenNames>Peter</givenNames><familyName>Vieregge</familyName><degrees>MD</degrees></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af10"><personName><givenNames>Anders O. H.</givenNames><familyName>Nygren</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au10" creatorRole="author" affiliationRef="#af11"><personName><givenNames>Christian</givenNames><familyName>Beetz</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au11" creatorRole="author" affiliationRef="#af1 #af2"><personName><givenNames>Katja</givenNames><familyName>Hedrich</familyName><degrees>PhD</degrees></personName></creator><creator xml:id="au12" creatorRole="author" affiliationRef="#af1" corresponding="yes"><personName><givenNames>Christine</givenNames><familyName>Klein</familyName><degrees>MD</degrees></personName></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="DE" type="organization"><unparsedAffiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="DE" type="organization"><unparsedAffiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="RS" type="organization"><unparsedAffiliation>Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences “Vinča”, Belgrade, Serbia</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="CA" type="organization"><unparsedAffiliation>Movement Disorders Centre, Toronto Western Hospital, Toronto, Canada</unparsedAffiliation></affiliation><affiliation xml:id="af5" countryCode="IT" type="organization"><unparsedAffiliation>Institute of Genetic Medicine, EURAC‐Research, Bolzano‐Bozen, Italy</unparsedAffiliation></affiliation><affiliation xml:id="af6" countryCode="US" type="organization"><unparsedAffiliation>Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA</unparsedAffiliation></affiliation><affiliation xml:id="af7" countryCode="DE" type="organization"><unparsedAffiliation>Department of Pediatric Neurology, Charité University Medicine Berlin, Berlin, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af8" countryCode="DE" type="organization"><unparsedAffiliation>Department of Pediatric Neurology, University Hospital Dresden, Dresden, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af9" countryCode="DE" type="organization"><unparsedAffiliation>Department of Neurology, Hospital Lippe‐Lemgo, Lemgo, Germany</unparsedAffiliation></affiliation><affiliation xml:id="af10" countryCode="NL" type="organization"><unparsedAffiliation>MRC‐Holland, Amsterdam, The Netherlands</unparsedAffiliation></affiliation><affiliation xml:id="af11" countryCode="DE" type="organization"><unparsedAffiliation>Institut of Clinical Chemistry and Laboratory Diagnostics, University Hospital of the Friedrich Schiller University, Jena, Germany</unparsedAffiliation></affiliation><affiliation xml:id="curr1" countryCode="DE"><unparsedAffiliation>Institute for Immunology, Ludwig‐Maximilian's University, Munich, Germany</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">multiplex ligation‐dependent probe amplification</keyword><keyword xml:id="kwd2">Parkinson's disease</keyword><keyword xml:id="kwd3">dopa‐responsive dystonia</keyword><keyword xml:id="kwd4">myoclonus‐dystonia</keyword><keyword xml:id="kwd5">exon rearrangements</keyword></keywordGroup><fundingInfo><fundingAgency>Deutsche Forschungsgemeinschaft</fundingAgency><fundingNumber>436 JUG 17/2/05</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Volkswagen Foundation</fundingAgency></fundingInfo><fundingInfo><fundingAgency>University of Lübeck</fundingAgency></fundingInfo><fundingInfo><fundingAgency>German Ministry of Education and Research</fundingAgency><fundingNumber>MDNET 01GM0302</fundingNumber></fundingInfo><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa‐responsive dystonia (DRD), and myoclonus‐dystonia (M‐D) should include screening for small sequence changes and for large exonic rearrangements in disease‐associated genes. In diagnostic and research settings, the latter is frequently omitted or performed by laborious and expensive quantitative real‐time PCR (qPCR). Our study aimed to evaluate the utility of a novel method, multiplex ligation‐dependent probe amplification (MLPA), in molecular diagnostics of movement disorders. We have analyzed, by MLPA, genomic DNA from 21 patients affected with PD, DRD, or M‐D, in which the presence of exon rearrangement(s) (n = 20) or of a specific point mutation (detectable by MLPA, n = 1) had been established previously by qPCR or sequencing. In parallel, we have studied, in a blinded fashion, DNA from 49 patients with an unknown mutational status. Exon rearrangements were evident in 20 samples with previously established mutations; in the 21st sample the known specific point mutation was detected. We conclude that MLPA represents a reliable method for large‐scale and cost‐effective gene dosage screening of various movement disorders genes. This finding reaches far beyond a simple technical advancement and has two major implications: (1) By improving the availability of comprehensive genetic testing, it supports clinicians in the establishment of a genetically defined diagnosis; (2) By enabling gene dosage testing of several genes simultaneously, it significantly facilitates the mutational analysis of large patient and control populations and thereby constitutes the prerequisite for meaningful phenotype–genotype correlations. © 2007 Movement Disorder Society</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><label>*</label><p>The first two authors contributed equally to this study.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation‐dependent probe amplification</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>MLPA in the Diagnostics of Movement Disorders</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Rapid and reliable detection of exon rearrangements in various movement disorders genes by multiplex ligation‐dependent probe amplification</title></titleInfo><name type="personal"><namePart type="given">Ana</namePart><namePart type="family">Djarmati</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation><description>The first two authors contributed equally to this study.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Miodrag</namePart><namePart type="family">Gužvić</namePart><namePart type="termsOfAddress">MSc</namePart><affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Laboratory for Radiobiology and Molecular Genetics, Institute of Nuclear Sciences “Vinča”, Belgrade, Serbia</affiliation><affiliation>Current Address: Institute for Immunology, Ludwig‐Maximilian's University, Munich, Germany</affiliation><description>The first two authors contributed equally to this study.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anne</namePart><namePart type="family">Grünewald</namePart><namePart type="termsOfAddress">MSc</namePart><affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anthony E.</namePart><namePart type="family">Lang</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Movement Disorders Centre, Toronto Western Hospital, Toronto, Canada</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter P.</namePart><namePart type="family">Pramstaller</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Institute of Genetic Medicine, EURAC‐Research, Bolzano‐Bozen, Italy</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">David K.</namePart><namePart type="family">Simon</namePart><namePart type="termsOfAddress">MD, PhD</namePart><affiliation>Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Angela M.</namePart><namePart type="family">Kaindl</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Pediatric Neurology, Charité University Medicine Berlin, Berlin, Germany</affiliation><affiliation>Department of Pediatric Neurology, University Hospital Dresden, Dresden, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Vieregge</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Department of Neurology, Hospital Lippe‐Lemgo, Lemgo, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Anders O. H.</namePart><namePart type="family">Nygren</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>MRC‐Holland, Amsterdam, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christian</namePart><namePart type="family">Beetz</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Institut of Clinical Chemistry and Laboratory Diagnostics, University Hospital of the Friedrich Schiller University, Jena, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Katja</namePart><namePart type="family">Hedrich</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</affiliation><affiliation>Department of Human Genetics, University of Lübeck, Lübeck, Germany</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Christine</namePart><namePart type="family">Klein</namePart><namePart type="termsOfAddress">MD</namePart><affiliation>Department of Neurology, University of Lübeck, Lübeck, Germany</affiliation><description>Correspondence: Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2007-09-15</dateIssued><dateCaptured encoding="w3cdtf">2006-10-23</dateCaptured><dateValid encoding="w3cdtf">2006-11-19</dateValid><copyrightDate encoding="w3cdtf">2007</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">2</extent><extent unit="tables">2</extent><extent unit="references">20</extent><extent unit="words">4262</extent></physicalDescription><abstract lang="en">Because of the occurrence of different types of mutations, comprehensive genetic testing for Parkinson's disease (PD), dopa‐responsive dystonia (DRD), and myoclonus‐dystonia (M‐D) should include screening for small sequence changes and for large exonic rearrangements in disease‐associated genes. In diagnostic and research settings, the latter is frequently omitted or performed by laborious and expensive quantitative real‐time PCR (qPCR). Our study aimed to evaluate the utility of a novel method, multiplex ligation‐dependent probe amplification (MLPA), in molecular diagnostics of movement disorders. We have analyzed, by MLPA, genomic DNA from 21 patients affected with PD, DRD, or M‐D, in which the presence of exon rearrangement(s) (n = 20) or of a specific point mutation (detectable by MLPA, n = 1) had been established previously by qPCR or sequencing. In parallel, we have studied, in a blinded fashion, DNA from 49 patients with an unknown mutational status. Exon rearrangements were evident in 20 samples with previously established mutations; in the 21st sample the known specific point mutation was detected. We conclude that MLPA represents a reliable method for large‐scale and cost‐effective gene dosage screening of various movement disorders genes. This finding reaches far beyond a simple technical advancement and has two major implications: (1) By improving the availability of comprehensive genetic testing, it supports clinicians in the establishment of a genetically defined diagnosis; (2) By enabling gene dosage testing of several genes simultaneously, it significantly facilitates the mutational analysis of large patient and control populations and thereby constitutes the prerequisite for meaningful phenotype–genotype correlations. © 2007 Movement Disorder Society</abstract><note type="funding">Deutsche Forschungsgemeinschaft - No. 436 JUG 17/2/05; </note><note type="funding">Volkswagen Foundation</note><note type="funding">University of Lübeck</note><note type="funding">German Ministry of Education and Research - No. MDNET 01GM0302; </note><subject lang="en"><genre>Keywords</genre><topic>multiplex ligation‐dependent probe amplification</topic><topic>Parkinson's disease</topic><topic>dopa‐responsive dystonia</topic><topic>myoclonus‐dystonia</topic><topic>exon rearrangements</topic></subject><relatedItem type="host"><titleInfo><title>Movement Disorders</title><subTitle>Official Journal of the Movement Disorder Society</subTitle></titleInfo><titleInfo type="abbreviated"><title>Mov. 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