Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement of FOXG1 appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus
Identifieur interne : 000293 ( Main/Corpus ); précédent : 000292; suivant : 000294Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement of FOXG1 appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus
Auteurs : Gijs W E. Santen ; Yu Sun ; Antoinet C J. Gijsbers ; Aurore Carré ; Maureen Holvoet ; Arie Van Haeringen ; Saskia A J. Lesnik Oberstein ; Akemi Tomoda ; Hiroyo Mabe ; Michel Polak ; Koenraad Devriendt ; Claudia A L. Ruivenkamp ; Emilia K. BijlsmaSource :
- Journal of Medical Genetics [ 0022-2593 ] ; 2012-06.
Abstract
Background Deletions including chromosome 14 band q13 have been linked to variable phenotypes. With current molecular methods the authors aim to elucidate a genotype–phenotype correlation by accurately determining the size and location of the deletions and the associated phenotype. Methods Here the authors report the molecular karyotyping and phenotypic description of seven patients with overlapping deletions including chromosome 14q13. Results The authors show that deletions including 14q13 result in a recognisable phenotype mainly due to haploinsufficiency of two genes (NKX2-1, PAX9). FOXG1 (on chromosome band 14q12) involvement seems to be the main determinant of phenotype severity. The patients in this study without FOXG1 involvement and deletions of up to 10 Mb have a relatively mild phenotype. The authors cannot explain why some patients in literature with overlapping but smaller deletions appear to have a more severe phenotype. A previously presumed association with holoprosencephaly could not be confirmed as none of the patients in this series had holoprosencephaly. Conclusions FOXG1 appears the main determinant of the severity of phenotypes resulting from deletions including 14q13. The collected data show no evidence for a locus for holoprosencephaly in the 14q13 region, but a locus for agenesis of the corpus callosum cannot be excluded.
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DOI: 10.1136/jmedgenet-2011-100721
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Santen</name><affiliation><mods:affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: santen@lumc.nl</mods:affiliation></affiliation></author><author><name sortKey="Sun, Yu" sort="Sun, Yu" uniqKey="Sun Y" first="Yu" last="Sun">Yu Sun</name><affiliation><mods:affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Gijsbers, Antoinet C J" sort="Gijsbers, Antoinet C J" uniqKey="Gijsbers A" first="Antoinet C J" last="Gijsbers">Antoinet C J. 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Ruivenkamp</name><affiliation><mods:affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Bijlsma, Emilia K" sort="Bijlsma, Emilia K" uniqKey="Bijlsma E" first="Emilia K" last="Bijlsma">Emilia K. Bijlsma</name><affiliation><mods:affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:19B70F75031B330BE13D2F2041DDC4671E05BF94</idno><date when="2012" year="2012">2012</date><idno type="doi">10.1136/jmedgenet-2011-100721</idno><idno type="url">https://api.istex.fr/document/19B70F75031B330BE13D2F2041DDC4671E05BF94/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000293</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement of FOXG1 appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus</title><author><name sortKey="Santen, Gijs W E" sort="Santen, Gijs W E" uniqKey="Santen G" first="Gijs W E" last="Santen">Gijs W E. Santen</name><affiliation><mods:affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: santen@lumc.nl</mods:affiliation></affiliation></author><author><name sortKey="Sun, Yu" sort="Sun, Yu" uniqKey="Sun Y" first="Yu" last="Sun">Yu Sun</name><affiliation><mods:affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Gijsbers, Antoinet C J" sort="Gijsbers, Antoinet C J" uniqKey="Gijsbers A" first="Antoinet C J" last="Gijsbers">Antoinet C J. Gijsbers</name><affiliation><mods:affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Carre, Aurore" sort="Carre, Aurore" uniqKey="Carre A" first="Aurore" last="Carré">Aurore Carré</name><affiliation><mods:affiliation>INSERM U 845, UMR 8200 CNRS, Institut Gustave Roussy, Villejuif, France</mods:affiliation></affiliation></author><author><name sortKey="Holvoet, Maureen" sort="Holvoet, Maureen" uniqKey="Holvoet M" first="Maureen" last="Holvoet">Maureen Holvoet</name><affiliation><mods:affiliation>Center for Human Genetics, University Hospital Leuven and K.U.Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Haeringen, Arie Van" sort="Haeringen, Arie Van" uniqKey="Haeringen A" first="Arie Van" last="Haeringen">Arie Van Haeringen</name><affiliation><mods:affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Clinical Genetics, Juliana Children's Hospital/HAGA Teaching Hospital, The Hague, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Lesnik Oberstein, Saskia A J" sort="Lesnik Oberstein, Saskia A J" uniqKey="Lesnik Oberstein S" first="Saskia A J" last="Lesnik Oberstein">Saskia A J. Lesnik Oberstein</name><affiliation><mods:affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Tomoda, Akemi" sort="Tomoda, Akemi" uniqKey="Tomoda A" first="Akemi" last="Tomoda">Akemi Tomoda</name><affiliation><mods:affiliation>Research Center for Child Mental Development, Graduate School of Medical Sciences, University of Fukui, Fukui, Japan</mods:affiliation></affiliation></author><author><name sortKey="Mabe, Hiroyo" sort="Mabe, Hiroyo" uniqKey="Mabe H" first="Hiroyo" last="Mabe">Hiroyo Mabe</name><affiliation><mods:affiliation>Department of Child Development, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan</mods:affiliation></affiliation></author><author><name sortKey="Polak, Michel" sort="Polak, Michel" uniqKey="Polak M" first="Michel" last="Polak">Michel Polak</name><affiliation><mods:affiliation>Université Paris Descartes, Sorbonne Paris Cité, INSERM U845, Pediatric endocrinology, AP-HP, Hôpital Necker Enfants Malades, Paris, France</mods:affiliation></affiliation></author><author><name sortKey="Devriendt, Koenraad" sort="Devriendt, Koenraad" uniqKey="Devriendt K" first="Koenraad" last="Devriendt">Koenraad Devriendt</name><affiliation><mods:affiliation>Center for Human Genetics, University Hospital Leuven and K.U.Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Ruivenkamp, Claudia A L" sort="Ruivenkamp, Claudia A L" uniqKey="Ruivenkamp C" first="Claudia A L" last="Ruivenkamp">Claudia A L. Ruivenkamp</name><affiliation><mods:affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</mods:affiliation></affiliation></author><author><name sortKey="Bijlsma, Emilia K" sort="Bijlsma, Emilia K" uniqKey="Bijlsma E" first="Emilia K" last="Bijlsma">Emilia K. Bijlsma</name><affiliation><mods:affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Journal of Medical Genetics</title><title level="j" type="abbrev">J Med Genet</title><idno type="ISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2012-06">2012-06</date><biblScope unit="volume">49</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="366">366</biblScope></imprint><idno type="ISSN">0022-2593</idno></series><idno type="istex">19B70F75031B330BE13D2F2041DDC4671E05BF94</idno><idno type="DOI">10.1136/jmedgenet-2011-100721</idno><idno type="href">jmedgenet-49-366.pdf</idno><idno type="ArticleID">jmedgenet-2011-100721</idno><idno type="PMID">22636604</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-2593</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Background Deletions including chromosome 14 band q13 have been linked to variable phenotypes. With current molecular methods the authors aim to elucidate a genotype–phenotype correlation by accurately determining the size and location of the deletions and the associated phenotype. Methods Here the authors report the molecular karyotyping and phenotypic description of seven patients with overlapping deletions including chromosome 14q13. Results The authors show that deletions including 14q13 result in a recognisable phenotype mainly due to haploinsufficiency of two genes (NKX2-1, PAX9). FOXG1 (on chromosome band 14q12) involvement seems to be the main determinant of phenotype severity. The patients in this study without FOXG1 involvement and deletions of up to 10 Mb have a relatively mild phenotype. The authors cannot explain why some patients in literature with overlapping but smaller deletions appear to have a more severe phenotype. A previously presumed association with holoprosencephaly could not be confirmed as none of the patients in this series had holoprosencephaly. Conclusions FOXG1 appears the main determinant of the severity of phenotypes resulting from deletions including 14q13. The collected data show no evidence for a locus for holoprosencephaly in the 14q13 region, but a locus for agenesis of the corpus callosum cannot be excluded.</div></front></TEI><istex><corpusName>bmj</corpusName><author><json:item><name>Gijs W E Santen</name><affiliations><json:string>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</json:string><json:string>E-mail: santen@lumc.nl</json:string></affiliations></json:item><json:item><name>Yu Sun</name><affiliations><json:string>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</json:string></affiliations></json:item><json:item><name>Antoinet C J Gijsbers</name><affiliations><json:string>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</json:string></affiliations></json:item><json:item><name>Aurore Carré</name><affiliations><json:string>INSERM U 845, UMR 8200 CNRS, Institut Gustave Roussy, Villejuif, France</json:string></affiliations></json:item><json:item><name>Maureen Holvoet</name><affiliations><json:string>Center for Human Genetics, University Hospital Leuven and K.U.Leuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Arie van Haeringen</name><affiliations><json:string>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</json:string><json:string>Department of Clinical Genetics, Juliana Children's Hospital/HAGA Teaching Hospital, The Hague, The Netherlands</json:string></affiliations></json:item><json:item><name>Saskia A J Lesnik Oberstein</name><affiliations><json:string>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</json:string></affiliations></json:item><json:item><name>Akemi Tomoda</name><affiliations><json:string>Research Center for Child Mental Development, Graduate School of Medical Sciences, University of Fukui, Fukui, Japan</json:string></affiliations></json:item><json:item><name>Hiroyo Mabe</name><affiliations><json:string>Department of Child Development, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan</json:string></affiliations></json:item><json:item><name>Michel Polak</name><affiliations><json:string>Université Paris Descartes, Sorbonne Paris Cité, INSERM U845, Pediatric endocrinology, AP-HP, Hôpital Necker Enfants Malades, Paris, France</json:string></affiliations></json:item><json:item><name>Koenraad Devriendt</name><affiliations><json:string>Center for Human Genetics, University Hospital Leuven and K.U.Leuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Claudia A L Ruivenkamp</name><affiliations><json:string>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</json:string></affiliations></json:item><json:item><name>Emilia K Bijlsma</name><affiliations><json:string>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Copy-number variation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Chromosome 14q13</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>NKX2-1</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>PAX9</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>FOXG1</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>holoprosencephaly</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>clinical genetics</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>adrenal disorders</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>pituitary disorders</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>genetics</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>genome-wide</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>molecular genetics</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>thyroid disease</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>endocrinology</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>neurology</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>aneuploidy</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>chromosomal</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>copy number</value></json:item></subject><language><json:string>eng</json:string></language><abstract>Background Deletions including chromosome 14 band q13 have been linked to variable phenotypes. With current molecular methods the authors aim to elucidate a genotype–phenotype correlation by accurately determining the size and location of the deletions and the associated phenotype. Methods Here the authors report the molecular karyotyping and phenotypic description of seven patients with overlapping deletions including chromosome 14q13. Results The authors show that deletions including 14q13 result in a recognisable phenotype mainly due to haploinsufficiency of two genes (NKX2-1, PAX9). FOXG1 (on chromosome band 14q12) involvement seems to be the main determinant of phenotype severity. The patients in this study without FOXG1 involvement and deletions of up to 10 Mb have a relatively mild phenotype. The authors cannot explain why some patients in literature with overlapping but smaller deletions appear to have a more severe phenotype. A previously presumed association with holoprosencephaly could not be confirmed as none of the patients in this series had holoprosencephaly. Conclusions FOXG1 appears the main determinant of the severity of phenotypes resulting from deletions including 14q13. The collected data show no evidence for a locus for holoprosencephaly in the 14q13 region, but a locus for agenesis of the corpus callosum cannot be excluded.</abstract><qualityIndicators><score>7.888</score><pdfVersion>1.4</pdfVersion><pdfPageSize>595.276 x 793.701 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>18</keywordCount><abstractCharCount>1368</abstractCharCount><pdfWordCount>5030</pdfWordCount><pdfCharCount>32188</pdfCharCount><pdfPageCount>7</pdfPageCount><abstractWordCount>199</abstractWordCount></qualityIndicators><title>Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement of FOXG1 appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus</title><pmid><json:string>22636604</json:string></pmid><genre><json:string>research-article</json:string></genre><host><volume>49</volume><pages><first>366</first></pages><issn><json:string>0022-2593</json:string></issn><issue>6</issue><genre></genre><language><json:string>unknown</json:string></language><eissn><json:string>1468-6244</json:string></eissn><title>Journal of Medical 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locus</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>BMJ Publishing Group Ltd</publisher><availability><p>BMJ</p></availability><date>2012-05-25</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement of FOXG1 appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus</title><author corresp="yes"><persName><forename type="first">Gijs W E</forename><surname>Santen</surname></persName><email>santen@lumc.nl</email><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation></author><author><persName><forename type="first">Yu</forename><surname>Sun</surname></persName><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation></author><author><persName><forename type="first">Antoinet C J</forename><surname>Gijsbers</surname></persName><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation></author><author><persName><forename type="first">Aurore</forename><surname>Carré</surname></persName><affiliation>INSERM U 845, UMR 8200 CNRS, Institut Gustave Roussy, Villejuif, France</affiliation></author><author><persName><forename type="first">Maureen</forename><surname>Holvoet</surname></persName><affiliation>Center for Human Genetics, University Hospital Leuven and K.U.Leuven, Leuven, Belgium</affiliation></author><author><persName><forename type="first">Arie van</forename><surname>Haeringen</surname></persName><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation><affiliation>Department of Clinical Genetics, Juliana Children's Hospital/HAGA Teaching Hospital, The Hague, The Netherlands</affiliation></author><author><persName><forename type="first">Saskia A J</forename><surname>Lesnik Oberstein</surname></persName><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation></author><author><persName><forename type="first">Akemi</forename><surname>Tomoda</surname></persName><affiliation>Research Center for Child Mental Development, Graduate School of Medical Sciences, University of Fukui, Fukui, Japan</affiliation></author><author><persName><forename type="first">Hiroyo</forename><surname>Mabe</surname></persName><affiliation>Department of Child Development, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan</affiliation></author><author><persName><forename type="first">Michel</forename><surname>Polak</surname></persName><affiliation>Université Paris Descartes, Sorbonne Paris Cité, INSERM U845, Pediatric endocrinology, AP-HP, Hôpital Necker Enfants Malades, Paris, France</affiliation></author><author><persName><forename type="first">Koenraad</forename><surname>Devriendt</surname></persName><affiliation>Center for Human Genetics, University Hospital Leuven and K.U.Leuven, Leuven, Belgium</affiliation></author><author><persName><forename type="first">Claudia A L</forename><surname>Ruivenkamp</surname></persName><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation></author><author><persName><forename type="first">Emilia K</forename><surname>Bijlsma</surname></persName><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation></author></analytic><monogr><title level="j">Journal of Medical Genetics</title><title level="j" type="abbrev">J Med Genet</title><idno type="JournalID">jmg</idno><idno type="pISSN">0022-2593</idno><idno type="eISSN">1468-6244</idno><imprint><publisher>BMJ Publishing Group Ltd</publisher><date type="published" when="2012-06"></date><biblScope unit="volume">49</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="366">366</biblScope></imprint></monogr><idno type="istex">19B70F75031B330BE13D2F2041DDC4671E05BF94</idno><idno type="DOI">10.1136/jmedgenet-2011-100721</idno><idno type="href">jmedgenet-49-366.pdf</idno><idno type="ArticleID">jmedgenet-2011-100721</idno><idno type="PMID">22636604</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2012-05-25</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Background Deletions including chromosome 14 band q13 have been linked to variable phenotypes. With current molecular methods the authors aim to elucidate a genotype–phenotype correlation by accurately determining the size and location of the deletions and the associated phenotype. Methods Here the authors report the molecular karyotyping and phenotypic description of seven patients with overlapping deletions including chromosome 14q13. Results The authors show that deletions including 14q13 result in a recognisable phenotype mainly due to haploinsufficiency of two genes (NKX2-1, PAX9). FOXG1 (on chromosome band 14q12) involvement seems to be the main determinant of phenotype severity. The patients in this study without FOXG1 involvement and deletions of up to 10 Mb have a relatively mild phenotype. The authors cannot explain why some patients in literature with overlapping but smaller deletions appear to have a more severe phenotype. A previously presumed association with holoprosencephaly could not be confirmed as none of the patients in this series had holoprosencephaly. Conclusions FOXG1 appears the main determinant of the severity of phenotypes resulting from deletions including 14q13. The collected data show no evidence for a locus for holoprosencephaly in the 14q13 region, but a locus for agenesis of the corpus callosum cannot be excluded.</p></abstract><textClass><keywords scheme="keyword"><list><head>heading</head><item><term>Copy-number variation</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>Chromosome 14q13</term></item><item><term>NKX2-1</term></item><item><term>PAX9</term></item><item><term>FOXG1</term></item><item><term>holoprosencephaly</term></item><item><term>clinical genetics</term></item><item><term>adrenal disorders</term></item><item><term>pituitary disorders</term></item><item><term>genetics</term></item><item><term>genome-wide</term></item><item><term>molecular genetics</term></item><item><term>thyroid disease</term></item><item><term>endocrinology</term></item><item><term>neurology</term></item><item><term>aneuploidy</term></item><item><term>chromosomal</term></item><item><term>copy number</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2012-05-25">Created</change><change when="2012-06">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/19B70F75031B330BE13D2F2041DDC4671E05BF94/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus bmj" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="no"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Archiving and Interchange DTD v2.3 20070202//EN" URI="archivearticle.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">jmedgenet</journal-id><journal-id journal-id-type="nlm-ta">J Med Genet</journal-id><journal-id journal-id-type="publisher-id">jmg</journal-id><journal-title>Journal of Medical Genetics</journal-title><abbrev-journal-title abbrev-type="publisher">J Med Genet</abbrev-journal-title><abbrev-journal-title>J Med Genet</abbrev-journal-title><issn pub-type="ppub">0022-2593</issn><issn pub-type="epub">1468-6244</issn><publisher><publisher-name>BMJ Publishing Group Ltd</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">jmedgenet-2011-100721</article-id><article-id pub-id-type="doi">10.1136/jmedgenet-2011-100721</article-id><article-id pub-id-type="other">jmedgenet;49/6/366</article-id><article-id pub-id-type="other">jmedgenet;jmedgenet-2011-100721</article-id><article-id pub-id-type="pmid">22636604</article-id><article-id pub-id-type="other">366</article-id><article-id pub-id-type="other">jmedgenet-2011-100721</article-id><article-categories><subj-group subj-group-type="heading"><subject>Copy-number variation</subject></subj-group><series-title>Original article</series-title></article-categories><title-group><article-title>Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement of <italic>FOXG1</italic> appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Santen</surname><given-names>Gijs W E</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Yu</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gijsbers</surname><given-names>Antoinet C J</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Carré</surname><given-names>Aurore</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Holvoet</surname><given-names>Maureen</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Haeringen</surname><given-names>Arie van</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Lesnik Oberstein</surname><given-names>Saskia A J</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Tomoda</surname><given-names>Akemi</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Mabe</surname><given-names>Hiroyo</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Polak</surname><given-names>Michel</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Devriendt</surname><given-names>Koenraad</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Ruivenkamp</surname><given-names>Claudia A L</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Bijlsma</surname><given-names>Emilia K</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</aff><aff id="aff2"><label>2</label>INSERM U 845, UMR 8200 CNRS, Institut Gustave Roussy, Villejuif, France</aff><aff id="aff3"><label>3</label>Center for Human Genetics, University Hospital Leuven and K.U.Leuven, Leuven, Belgium</aff><aff id="aff4"><label>4</label>Department of Clinical Genetics, Juliana Children's Hospital/HAGA Teaching Hospital, The Hague, The Netherlands</aff><aff id="aff5"><label>5</label>Research Center for Child Mental Development, Graduate School of Medical Sciences, University of Fukui, Fukui, Japan</aff><aff id="aff6"><label>6</label>Department of Child Development, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan</aff><aff id="aff7"><label>7</label>Université Paris Descartes, Sorbonne Paris Cité, INSERM U845, Pediatric endocrinology, AP-HP, Hôpital Necker Enfants Malades, Paris, France</aff><author-notes><corresp><label>Correspondence to</label> Dr Gijs W E Santen, Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Albinusdreef 2, Postbus 9600, Leiden 2300 RC, The Netherlands; <email>santen@lumc.nl</email></corresp></author-notes><pub-date pub-type="epub-original"><day>25</day><month>5</month><year>2012</year></pub-date><pub-date pub-type="ppub"><month>6</month><year>2012</year></pub-date><pub-date pub-type="epub"><day>25</day><month>5</month><year>2012</year></pub-date><volume>49</volume><volume-id pub-id-type="other">49</volume-id><volume-id pub-id-type="other">49</volume-id><issue>6</issue><issue-id pub-id-type="other">jmedgenet;49/6</issue-id><issue-id pub-id-type="other">6</issue-id><issue-id pub-id-type="other">49/6</issue-id><fpage>366</fpage><history><date date-type="received"><day>9</day><month>2</month><year>2012</year></date><date date-type="accepted"><day>2</day><month>4</month><year>2012</year></date></history><permissions><copyright-statement>© 2012, Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.</copyright-statement><copyright-year>2012</copyright-year></permissions><self-uri content-type="pdf" xlink:role="full-text" xlink:href="jmedgenet-49-366.pdf"></self-uri><abstract><sec><title>Background</title><p>Deletions including chromosome 14 band q13 have been linked to variable phenotypes. With current molecular methods the authors aim to elucidate a genotype–phenotype correlation by accurately determining the size and location of the deletions and the associated phenotype.</p></sec><sec><title>Methods</title><p>Here the authors report the molecular karyotyping and phenotypic description of seven patients with overlapping deletions including chromosome 14q13.</p></sec><sec><title>Results</title><p>The authors show that deletions including 14q13 result in a recognisable phenotype mainly due to haploinsufficiency of two genes (<italic>NKX2-1</italic>, <italic>PAX9</italic>). <italic>FOXG1</italic> (on chromosome band 14q12) involvement seems to be the main determinant of phenotype severity. The patients in this study without <italic>FOXG1</italic> involvement and deletions of up to 10 Mb have a relatively mild phenotype. The authors cannot explain why some patients in literature with overlapping but smaller deletions appear to have a more severe phenotype. A previously presumed association with holoprosencephaly could not be confirmed as none of the patients in this series had holoprosencephaly.</p></sec><sec><title>Conclusions</title><p><italic>FOXG1</italic> appears the main determinant of the severity of phenotypes resulting from deletions including 14q13. The collected data show no evidence for a locus for holoprosencephaly in the 14q13 region, but a locus for agenesis of the corpus callosum cannot be excluded.</p></sec></abstract><kwd-group><kwd>Chromosome 14q13</kwd><kwd>NKX2-1</kwd><kwd>PAX9</kwd><kwd>FOXG1</kwd><kwd>holoprosencephaly</kwd><kwd>clinical genetics</kwd><kwd>adrenal disorders</kwd><kwd>pituitary disorders</kwd><kwd>genetics</kwd><kwd>genome-wide</kwd><kwd>molecular genetics</kwd><kwd>thyroid disease</kwd><kwd>endocrinology</kwd><kwd>neurology</kwd><kwd>aneuploidy</kwd><kwd>chromosomal</kwd><kwd>copy number</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><partName>Original article</partName><title>Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement of FOXG1 appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><partName>Original article</partName><title>Further delineation of the phenotype of chromosome 14q13 deletions: (positional) involvement of FOXG1 appears the main determinant of phenotype severity, with no evidence for a holoprosencephaly locus</title></titleInfo><name type="personal" displayLabel="corresp"><namePart type="given">Gijs W E</namePart><namePart type="family">Santen</namePart><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation><affiliation>E-mail: santen@lumc.nl</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Yu</namePart><namePart type="family">Sun</namePart><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Antoinet C J</namePart><namePart type="family">Gijsbers</namePart><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Aurore</namePart><namePart type="family">Carré</namePart><affiliation>INSERM U 845, UMR 8200 CNRS, Institut Gustave Roussy, Villejuif, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Maureen</namePart><namePart type="family">Holvoet</namePart><affiliation>Center for Human Genetics, University Hospital Leuven and K.U.Leuven, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Arie van</namePart><namePart type="family">Haeringen</namePart><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation><affiliation>Department of Clinical Genetics, Juliana Children's Hospital/HAGA Teaching Hospital, The Hague, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Saskia A J</namePart><namePart type="family">Lesnik Oberstein</namePart><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Akemi</namePart><namePart type="family">Tomoda</namePart><affiliation>Research Center for Child Mental Development, Graduate School of Medical Sciences, University of Fukui, Fukui, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Hiroyo</namePart><namePart type="family">Mabe</namePart><affiliation>Department of Child Development, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michel</namePart><namePart type="family">Polak</namePart><affiliation>Université Paris Descartes, Sorbonne Paris Cité, INSERM U845, Pediatric endocrinology, AP-HP, Hôpital Necker Enfants Malades, Paris, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Koenraad</namePart><namePart type="family">Devriendt</namePart><affiliation>Center for Human Genetics, University Hospital Leuven and K.U.Leuven, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Claudia A L</namePart><namePart type="family">Ruivenkamp</namePart><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Emilia K</namePart><namePart type="family">Bijlsma</namePart><affiliation>Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Leiden, The Netherlands</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article">research-article</genre><subject><genre>heading</genre><topic>Copy-number variation</topic></subject><originInfo><publisher>BMJ Publishing Group Ltd</publisher><dateIssued encoding="w3cdtf">2012-06</dateIssued><dateCreated encoding="w3cdtf">2012-05-25</dateCreated><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Background Deletions including chromosome 14 band q13 have been linked to variable phenotypes. With current molecular methods the authors aim to elucidate a genotype–phenotype correlation by accurately determining the size and location of the deletions and the associated phenotype. Methods Here the authors report the molecular karyotyping and phenotypic description of seven patients with overlapping deletions including chromosome 14q13. Results The authors show that deletions including 14q13 result in a recognisable phenotype mainly due to haploinsufficiency of two genes (NKX2-1, PAX9). FOXG1 (on chromosome band 14q12) involvement seems to be the main determinant of phenotype severity. The patients in this study without FOXG1 involvement and deletions of up to 10 Mb have a relatively mild phenotype. The authors cannot explain why some patients in literature with overlapping but smaller deletions appear to have a more severe phenotype. A previously presumed association with holoprosencephaly could not be confirmed as none of the patients in this series had holoprosencephaly. Conclusions FOXG1 appears the main determinant of the severity of phenotypes resulting from deletions including 14q13. The collected data show no evidence for a locus for holoprosencephaly in the 14q13 region, but a locus for agenesis of the corpus callosum cannot be excluded.</abstract><subject><genre>Keywords</genre><topic>Chromosome 14q13</topic><topic>NKX2-1</topic><topic>PAX9</topic><topic>FOXG1</topic><topic>holoprosencephaly</topic><topic>clinical genetics</topic><topic>adrenal disorders</topic><topic>pituitary disorders</topic><topic>genetics</topic><topic>genome-wide</topic><topic>molecular genetics</topic><topic>thyroid disease</topic><topic>endocrinology</topic><topic>neurology</topic><topic>aneuploidy</topic><topic>chromosomal</topic><topic>copy number</topic></subject><relatedItem type="host"><titleInfo><title>Journal of Medical Genetics</title></titleInfo><titleInfo type="abbreviated"><title>J Med Genet</title></titleInfo><identifier type="ISSN">0022-2593</identifier><identifier type="eISSN">1468-6244</identifier><identifier type="JournalID">jmg</identifier><identifier type="JournalID-hwp">jmedgenet</identifier><identifier type="JournalID-nlm-ta">J Med Genet</identifier><part><date>2012</date><detail type="volume"><caption>vol.</caption><number>49</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>366</start></extent></part></relatedItem><identifier type="istex">19B70F75031B330BE13D2F2041DDC4671E05BF94</identifier><identifier type="DOI">10.1136/jmedgenet-2011-100721</identifier><identifier type="href">jmedgenet-49-366.pdf</identifier><identifier type="ArticleID">jmedgenet-2011-100721</identifier><identifier type="PMID">22636604</identifier><accessCondition type="use and reproduction" contentType="Copyright">© 2012, Published by the BMJ Publishing Group Limited. 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