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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Distinct Effects of Allelic <italic>NFIX</italic> Mutations on Nonsense-Mediated mRNA Decay Engender Either a Sotos-like or a Marshall-Smith Syndrome</title><author><name sortKey="Malan, Valerie" sort="Malan, Valerie" uniqKey="Malan V" first="Valérie" last="Malan">Valérie Malan</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Rajan, Diana" sort="Rajan, Diana" uniqKey="Rajan D" first="Diana" last="Rajan">Diana Rajan</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Thomas, Sophie" sort="Thomas, Sophie" uniqKey="Thomas S" first="Sophie" last="Thomas">Sophie Thomas</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Shaw, Adam C" sort="Shaw, Adam C" uniqKey="Shaw A" first="Adam C." last="Shaw">Adam C. Shaw</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Louis Dit Picard, Helene" sort="Louis Dit Picard, Helene" uniqKey="Louis Dit Picard H" first="Hélène" last="Louis Dit Picard">Hélène Louis Dit Picard</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Layet, Valerie" sort="Layet, Valerie" uniqKey="Layet V" first="Valérie" last="Layet">Valérie Layet</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Till, Marianne" sort="Till, Marianne" uniqKey="Till M" first="Marianne" last="Till">Marianne Till</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Van Haeringen, Arie" sort="Van Haeringen, Arie" uniqKey="Van Haeringen A" first="Arie" last="Van Haeringen">Arie Van Haeringen</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Mortier, Geert" sort="Mortier, Geert" uniqKey="Mortier G" first="Geert" last="Mortier">Geert Mortier</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Nampoothiri, Sheela" sort="Nampoothiri, Sheela" uniqKey="Nampoothiri S" first="Sheela" last="Nampoothiri">Sheela Nampoothiri</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation></author><author><name sortKey="Puselji, Silvija" sort="Puselji, Silvija" uniqKey="Puselji S" first="Silvija" last="Pušelji">Silvija Pušelji</name><affiliation><nlm:aff id="aff9"></nlm:aff></affiliation></author><author><name sortKey="Legeai Mallet, Laurence" sort="Legeai Mallet, Laurence" uniqKey="Legeai Mallet L" first="Laurence" last="Legeai-Mallet">Laurence Legeai-Mallet</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Carter, Nigel P" sort="Carter, Nigel P" uniqKey="Carter N" first="Nigel P." last="Carter">Nigel P. Carter</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Vekemans, Michel" sort="Vekemans, Michel" uniqKey="Vekemans M" first="Michel" last="Vekemans">Michel Vekemans</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Hennekam, Raoul C" sort="Hennekam, Raoul C" uniqKey="Hennekam R" first="Raoul C." last="Hennekam">Raoul C. Hennekam</name><affiliation><nlm:aff id="aff10"></nlm:aff></affiliation></author><author><name sortKey="Colleaux, Laurence" sort="Colleaux, Laurence" uniqKey="Colleaux L" first="Laurence" last="Colleaux">Laurence Colleaux</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Cormier Daire, Valerie" sort="Cormier Daire, Valerie" uniqKey="Cormier Daire V" first="Valérie" last="Cormier-Daire">Valérie Cormier-Daire</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20673863</idno><idno type="pmc">2917711</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917711</idno><idno type="RBID">PMC:2917711</idno><idno type="doi">10.1016/j.ajhg.2010.07.001</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000171</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Distinct Effects of Allelic <italic>NFIX</italic> Mutations on Nonsense-Mediated mRNA Decay Engender Either a Sotos-like or a Marshall-Smith Syndrome</title><author><name sortKey="Malan, Valerie" sort="Malan, Valerie" uniqKey="Malan V" first="Valérie" last="Malan">Valérie Malan</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Rajan, Diana" sort="Rajan, Diana" uniqKey="Rajan D" first="Diana" last="Rajan">Diana Rajan</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Thomas, Sophie" sort="Thomas, Sophie" uniqKey="Thomas S" first="Sophie" last="Thomas">Sophie Thomas</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Shaw, Adam C" sort="Shaw, Adam C" uniqKey="Shaw A" first="Adam C." last="Shaw">Adam C. Shaw</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Louis Dit Picard, Helene" sort="Louis Dit Picard, Helene" uniqKey="Louis Dit Picard H" first="Hélène" last="Louis Dit Picard">Hélène Louis Dit Picard</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Layet, Valerie" sort="Layet, Valerie" uniqKey="Layet V" first="Valérie" last="Layet">Valérie Layet</name><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation></author><author><name sortKey="Till, Marianne" sort="Till, Marianne" uniqKey="Till M" first="Marianne" last="Till">Marianne Till</name><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation></author><author><name sortKey="Van Haeringen, Arie" sort="Van Haeringen, Arie" uniqKey="Van Haeringen A" first="Arie" last="Van Haeringen">Arie Van Haeringen</name><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Mortier, Geert" sort="Mortier, Geert" uniqKey="Mortier G" first="Geert" last="Mortier">Geert Mortier</name><affiliation><nlm:aff id="aff7"></nlm:aff></affiliation></author><author><name sortKey="Nampoothiri, Sheela" sort="Nampoothiri, Sheela" uniqKey="Nampoothiri S" first="Sheela" last="Nampoothiri">Sheela Nampoothiri</name><affiliation><nlm:aff id="aff8"></nlm:aff></affiliation></author><author><name sortKey="Puselji, Silvija" sort="Puselji, Silvija" uniqKey="Puselji S" first="Silvija" last="Pušelji">Silvija Pušelji</name><affiliation><nlm:aff id="aff9"></nlm:aff></affiliation></author><author><name sortKey="Legeai Mallet, Laurence" sort="Legeai Mallet, Laurence" uniqKey="Legeai Mallet L" first="Laurence" last="Legeai-Mallet">Laurence Legeai-Mallet</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Carter, Nigel P" sort="Carter, Nigel P" uniqKey="Carter N" first="Nigel P." last="Carter">Nigel P. Carter</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Vekemans, Michel" sort="Vekemans, Michel" uniqKey="Vekemans M" first="Michel" last="Vekemans">Michel Vekemans</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Munnich, Arnold" sort="Munnich, Arnold" uniqKey="Munnich A" first="Arnold" last="Munnich">Arnold Munnich</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Hennekam, Raoul C" sort="Hennekam, Raoul C" uniqKey="Hennekam R" first="Raoul C." last="Hennekam">Raoul C. Hennekam</name><affiliation><nlm:aff id="aff10"></nlm:aff></affiliation></author><author><name sortKey="Colleaux, Laurence" sort="Colleaux, Laurence" uniqKey="Colleaux L" first="Laurence" last="Colleaux">Laurence Colleaux</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Cormier Daire, Valerie" sort="Cormier Daire, Valerie" uniqKey="Cormier Daire V" first="Valérie" last="Cormier-Daire">Valérie Cormier-Daire</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">American Journal of Human Genetics</title><idno type="ISSN">0002-9297</idno><idno type="eISSN">1537-6605</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>By using a combination of array comparative genomic hybridization and a candidate gene approach, we identified nuclear factor I/X (<italic>NFIX</italic>) deletions or nonsense mutation in three sporadic cases of a Sotos-like overgrowth syndrome with advanced bone age, macrocephaly, developmental delay, scoliosis, and unusual facies. Unlike the aforementioned human syndrome, <italic>Nfix</italic>-deficient mice are unable to gain weight and die in the first 3 postnatal weeks, while they also present with a spinal deformation and decreased bone mineralization. These features prompted us to consider <italic>NFIX</italic> as a candidate gene for Marshall-Smith syndrome (MSS), a severe malformation syndrome characterized by failure to thrive, respiratory insufficiency, accelerated osseous maturation, kyphoscoliosis, osteopenia, and unusual facies. Distinct frameshift and splice <italic>NFIX</italic> mutations that escaped nonsense-mediated mRNA decay (NMD) were identified in nine MSS subjects. NFIX belongs to the Nuclear factor one (NFI) family of transcription factors, but its specific function is presently unknown. We demonstrate that <italic>NFIX</italic> is normally expressed prenatally during human brain development and skeletogenesis. These findings demonstrate that allelic <italic>NFIX</italic> mutations trigger distinct phenotypes, depending specifically on their impact on NMD.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Am J Hum Genet</journal-id><journal-title>American Journal of Human Genetics</journal-title><issn pub-type="ppub">0002-9297</issn><issn pub-type="epub">1537-6605</issn><publisher><publisher-name>Elsevier</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">20673863</article-id><article-id pub-id-type="pmc">2917711</article-id><article-id pub-id-type="publisher-id">AJHG693</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2010.07.001</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Distinct Effects of Allelic <italic>NFIX</italic> Mutations on Nonsense-Mediated mRNA Decay Engender Either a Sotos-like or a Marshall-Smith Syndrome</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Malan</surname><given-names>Valérie</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Rajan</surname><given-names>Diana</given-names></name><xref rid="aff2" ref-type="aff">2</xref><xref rid="fn1" ref-type="fn">11</xref></contrib><contrib contrib-type="author"><name><surname>Thomas</surname><given-names>Sophie</given-names></name><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn1" ref-type="fn">11</xref></contrib><contrib contrib-type="author"><name><surname>Shaw</surname><given-names>Adam C.</given-names></name><xref rid="aff3" ref-type="aff">3</xref></contrib><contrib contrib-type="author"><name><surname>Louis dit Picard</surname><given-names>Hélène</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Layet</surname><given-names>Valérie</given-names></name><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Till</surname><given-names>Marianne</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>van Haeringen</surname><given-names>Arie</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Mortier</surname><given-names>Geert</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Nampoothiri</surname><given-names>Sheela</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Pušeljić</surname><given-names>Silvija</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Legeai-Mallet</surname><given-names>Laurence</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Carter</surname><given-names>Nigel P.</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Vekemans</surname><given-names>Michel</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Munnich</surname><given-names>Arnold</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Hennekam</surname><given-names>Raoul C.</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Colleaux</surname><given-names>Laurence</given-names></name><email>laurence.colleaux@inserm.fr</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn2" ref-type="fn">12</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Cormier-Daire</surname><given-names>Valérie</given-names></name><email>valerie.cormier-daire@inserm.fr</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="fn2" ref-type="fn">12</xref><xref rid="cor2" ref-type="corresp">∗∗</xref></contrib></contrib-group><aff id="aff1"><addr-line><sup>1</sup>INSERM U781 and Département de Génétique, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris 75015, France</addr-line></aff><aff id="aff2"><addr-line><sup>2</sup>The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, Cambridge, UK</addr-line></aff><aff id="aff3"><addr-line><sup>3</sup>Clinical and Molecular Genetics Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK</addr-line></aff><aff id="aff4"><addr-line><sup>4</sup>Service de Génétique clinique, CH Le Havre, 55 bis rue Gustave Flaubert, Le Havre 76600, France</addr-line></aff><aff id="aff5"><addr-line><sup>5</sup>Service de Génétique clinique, Hôpital Femme Mère Enfant, Groupement Hospitalier Est, 59 boulevard Pinel, Bron 69677, France</addr-line></aff><aff id="aff6"><addr-line><sup>6</sup>Department of Clinical Genetics, LUMC Leiden University Medical Center, Postbus 9600, Leiden 2300 RC, The Netherlands</addr-line></aff><aff id="aff7"><addr-line><sup>7</sup>Center for Medical Genetics, Antwerp University Hospital, Prins Boudewijnlaan 43, B-2650 Edegem, Belgium</addr-line></aff><aff id="aff8"><addr-line><sup>8</sup>Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Center, AIMS Ponekkara PO, Cochin 682041 Kerala, India</addr-line></aff><aff id="aff9"><addr-line><sup>9</sup>Pediatrics Clinic, Clinical Hospital Centre Osijek (KBC), J. Huttlera 4, Osijek 31 000, Croatia</addr-line></aff><aff id="aff10"><addr-line><sup>10</sup>Department of Clinical Genetics, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands</addr-line></aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>laurence.colleaux@inserm.fr</email></corresp><corresp id="cor2"><label>∗∗</label>Corresponding author <email>valerie.cormier-daire@inserm.fr</email></corresp><fn id="fn1"><label>11</label><p>These authors contributed equally to this work</p></fn><fn id="fn2"><label>12</label><p>These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="ppub"><day>13</day><month>8</month><year>2010</year></pub-date><volume>87</volume><issue>2</issue><fpage>189</fpage><lpage>198</lpage><history><date date-type="received"><day>18</day><month>6</month><year>2010</year></date><date date-type="rev-recd"><day>6</day><month>7</month><year>2010</year></date><date date-type="accepted"><day>7</day><month>7</month><year>2010</year></date></history><permissions><copyright-statement>© 2010 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved..</copyright-statement><copyright-year>2010</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder><license><p>This document may be redistributed and reused, subject to <ext-link ext-link-type="uri" xlink:href="http://www.elsevier.com/wps/find/authorsview.authors/supplementalterms1.0">certain conditions</ext-link>.</p></license></permissions><abstract><p>By using a combination of array comparative genomic hybridization and a candidate gene approach, we identified nuclear factor I/X (<italic>NFIX</italic>) deletions or nonsense mutation in three sporadic cases of a Sotos-like overgrowth syndrome with advanced bone age, macrocephaly, developmental delay, scoliosis, and unusual facies. Unlike the aforementioned human syndrome, <italic>Nfix</italic>-deficient mice are unable to gain weight and die in the first 3 postnatal weeks, while they also present with a spinal deformation and decreased bone mineralization. These features prompted us to consider <italic>NFIX</italic> as a candidate gene for Marshall-Smith syndrome (MSS), a severe malformation syndrome characterized by failure to thrive, respiratory insufficiency, accelerated osseous maturation, kyphoscoliosis, osteopenia, and unusual facies. Distinct frameshift and splice <italic>NFIX</italic> mutations that escaped nonsense-mediated mRNA decay (NMD) were identified in nine MSS subjects. NFIX belongs to the Nuclear factor one (NFI) family of transcription factors, but its specific function is presently unknown. We demonstrate that <italic>NFIX</italic> is normally expressed prenatally during human brain development and skeletogenesis. These findings demonstrate that allelic <italic>NFIX</italic> mutations trigger distinct phenotypes, depending specifically on their impact on NMD.</p></abstract></article-meta></front><floats-wrap><fig id="fig1"><label>Figure 1</label><caption><p>Genetic Analyses of Patients with Syndromic Overgrowth</p><p>(A) The figure shows the Ensembl display of the 19p13.2p13.3 region. Position of nonoverlapping <italic>NFIX</italic> deletions detected in patients A and B are represented by squares. For patient A, we found the proximal and distal breakpoints at 12 898 751 and 13 006 539 bp, respectively. For patient B, we found the proximal and distal breakpoints at 13 022 358 bp and 13 126 508 bp, respectively.</p><p>(B) The diagram shows the different mutations identified in <italic>NFIX</italic> genomic DNA. Open boxes represent untranslated regions and filled boxes represent coding regions. Mutation in green corresponds to the Sotos-like case while those in red indicate mutations found in MSS cases.</p><p>(C) Representative sequence traces of exon 3 in genomic DNA (top) or cDNA (bottom) of patient C (c.568C>T).</p><p>(D) Representative sequence traces of exon 8 sequences from genomic DNA (top) or cDNA (bottom) of patient F (c.1243 delG).</p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Front Views of the Three Overgrowth Syndrome Patients</p><p>Note the high forehead, long narrow face (patients A and C), and slender habitus.</p></caption><graphic xlink:href="gr2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>Pictures and Hand and Foot X-Rays of Patients with Marshall-Smith Syndrome</p><p>Facial features of the nine patients with Marshall-Smith syndrome (A–I) and hand X-rays at 1 year (J) and 4 years (K) of age and foot X-rays at 1 year of age (L). Note the high forehead, proptosis, underdeveloped midface, the advanced carpal and tarsal ossification, and the abnormal wide, bullet-shaped phalanges.</p></caption><graphic xlink:href="gr3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Pattern of <italic>NFIX</italic> Expression in Early Human Development and Fetal Epiphyseal Growth Plate</p><p>(A–G) Adjacent sections of human embryos and fetuses treated with antisense (A–C, E–G) or with control sense (D) riboprobes.</p><p>(A) Carnegie stage 17 (CS17) human embryo section.</p><p>(B–D) CS19 human embryo sections.</p><p>(E) Frontal section of a fetal (22WG) brain.</p><p>(F and G) Sagittal section of a fetal (14WG) hand.</p><p>The hybridization with control sense probe does not give any signal (D).</p><p>Note the expression in the neuroepithelium of the prosencephalon, the mesencephalon, the rhombencephalon, and the spinal cord as well as in the cranial and dorsal root ganglia.</p><p>Abbreviations: Ah, Ammon's horn; c, cerebral cortex; co, cochlea; dg, dentate gyrus; di, diencephalon; drg, dorsal root ganglia; fv, fourth ventricule; h, heart; hu, humerus; ie, inner ear; la, lateral ventricule; li, liver; lu, lung; M, mesencephalon; me, mesonephros; nt, neuroepithelium of the neural tube; oe, olfactory epithelium; op, optic stalk; ot, otic vesicle; p, pons; pa, pharingial arch; sca, scapula; st, stomach; T, Telencephalon; th, thalamus; V, trigeminal ganglia; ve, cartilage primordia of vertebrae.</p><p>(H–M) NFIX immunohistochemostry performed in 1-week-old mice (H), 2-week-old mice (I), 3-week-old mice (J), 4-week-old mice (K), 5-week-old mice (L), and 20 weeks of gestation human fetus (M). Note the restricted expression in the prehypertrophic chondrocytes and the expression in bone.</p><p>Abbreviations: of, ossification front, hy, hypertrophic zone; PHy, prehypertrophic zone; Pro, proliferative zone.</p></caption><graphic xlink:href="gr4"></graphic></fig><table-wrap position="float" id="tbl1"><label>Table 1</label><caption><p>Clinical Details of Patients with 19p13.1 Monosomy and c.568C>T <italic>NFI-X</italic> Mutation</p></caption><table frame="hsides" rules="groups"><thead><tr><th></th><th><bold>Patient A</bold></th><th><bold>Patient B</bold></th><th><bold>Patient C</bold></th></tr></thead><tbody><tr><td>NFIX deletion/mutation</td><td>del 19p13.3</td><td>del 19p13.3</td><td>c.568C>T</td></tr><tr><td>Age at the last examination (yr)</td><td>14</td><td>10</td><td>27</td></tr><tr><td>Sex</td><td>M</td><td>M</td><td>F</td></tr><tr><td>Age mother/father (yr)</td><td>31/33</td><td>25/30</td><td>31/31</td></tr><tr><td>Ethnic origin</td><td>French</td><td>French</td><td>French</td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td colspan="4"><bold>Prenatal growth</bold></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td>Birth weight (g) (centile)</td><td>4500 (>95)</td><td>3110 (10–50)</td><td>3600 (50–90)</td></tr><tr><td>Birth height (cm) (centile)</td><td>53 (95)</td><td>49 (50)</td><td>52 (95)</td></tr><tr><td>OFC (cm) (centile)</td><td>38 (>95)</td><td>33.5 (10)</td><td>37.5 (>95)</td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td><bold>Feeding problems in neonatal period</bold></td><td>+</td><td>+</td><td></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td colspan="4"><bold>Postnatal growth</bold></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td>Height > P98</td><td>+</td><td>+</td><td>+</td></tr><tr><td>OFC > P98</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Height-weight ratio < P25</td><td>+</td><td>+</td><td></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td colspan="4"><bold>Developmental characteristics</bold></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td>Mental retardation</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Speech delay</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Autistic traits</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Behavioral anomalies</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Motor retardation</td><td>+</td><td></td><td></td></tr><tr><td>Hypotonia</td><td>+</td><td>+</td><td></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td colspan="4"><bold>Brain MRI</bold></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td>Ventricular dilatation/hypoplasia corpus callosum</td><td>+</td><td></td><td></td></tr><tr><td>Ventricular dilatation</td><td></td><td></td><td>+</td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td colspan="4"><bold>Craniofacial features</bold></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td>Long/narrow face</td><td>+</td><td>+</td><td>+</td></tr><tr><td>High forehead</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Down-slanting palpebral fissures</td><td>+</td><td></td><td>+</td></tr><tr><td>Small mouth</td><td>+</td><td></td><td>+</td></tr><tr><td>Everted lower lip</td><td>+</td><td></td><td>+</td></tr><tr><td>Prognathia</td><td>+</td><td></td><td></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td colspan="4"><bold>Eyes</bold></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td>Hypermotropia</td><td>+</td><td>+</td><td></td></tr><tr><td>Strabismus</td><td>+</td><td></td><td>+</td></tr><tr><td>Nystagmus</td><td></td><td></td><td>+</td></tr><tr><td>Astigmatism</td><td></td><td>+</td><td></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td colspan="4"><bold>Musculo-skeletal abnormalities</bold></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td>Pectus excavatum</td><td>+</td><td>+</td><td></td></tr><tr><td>Scoliosis</td><td>+</td><td></td><td>+</td></tr><tr><td>Advanced bone age</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Abdominal wall hypotonia</td><td>+</td><td></td><td>+</td></tr><tr><td>Coxa valga</td><td>+</td><td>+</td><td></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td colspan="4"><bold>Hand/foot abnormalities</bold></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td>Long fingers</td><td>+</td><td>+</td><td></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td colspan="4"><bold>Other abnormalities</bold></td></tr><tr><td colspan="4"><hr></hr></td></tr><tr><td>Malformed nails</td><td>+</td><td></td><td></td></tr><tr><td>Premature eruption of teeth</td><td>+</td><td></td><td></td></tr><tr><td>Generalized livedo</td><td></td><td>+</td><td></td></tr></tbody></table></table-wrap><table-wrap position="float" id="tbl2"><label>Table 2</label><caption><p>Clinical Details of the Nine Patients with Marshall-Smith Syndrome</p></caption><table frame="hsides" rules="groups"><thead><tr><th><bold>Patient</bold><hr></hr></th><th><bold>1</bold><hr></hr></th><th><bold>2</bold><hr></hr></th><th><bold>3</bold><hr></hr></th><th><bold>4</bold><hr></hr></th><th><bold>5</bold><hr></hr></th><th><bold>6</bold><hr></hr></th><th><bold>7</bold><hr></hr></th><th><bold>8</bold><hr></hr></th><th><bold>9</bold><hr></hr></th></tr><tr><th><bold>NFIX mutation</bold></th><th><bold>c.955+1G>A</bold></th><th><bold>c.955+1G>T</bold></th><th><bold>c.1011_1012 delTC</bold></th><th><bold>c.1037_1038 insT</bold></th><th><bold>c.1008_1012 delCTCTC</bold></th><th><bold>c.1048_1049 insC</bold></th><th><bold>c.1243 delG</bold></th><th><bold>c.994_995 insT</bold></th><th><bold>c.959_960 insC</bold></th></tr></thead><tbody><tr><td colspan="10"><bold>Epidemiology</bold></td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td>Gender</td><td>M</td><td>F</td><td>M</td><td>M</td><td>F</td><td>F</td><td>M</td><td>F</td><td>M</td></tr><tr><td>Age at last examination</td><td>3 weeks<xref rid="tblfn1" ref-type="table-fn">a</xref></td><td>6 months</td><td>26 months</td><td>3 years</td><td>6 years</td><td>7 years</td><td>7 years</td><td>16 years</td><td>21 years</td></tr><tr><td>Ethnic origin</td><td>Belgium</td><td>Croatia</td><td>India</td><td>Netherlands</td><td>Brazil</td><td>Portugal</td><td>France</td><td>UK</td><td>UK</td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td colspan="10"><bold>Growth</bold></td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td>Birth weight (g)</td><td>2600</td><td>3400</td><td>2950</td><td>2975</td><td></td><td>1590</td><td>3230</td><td>2800</td><td>3860</td></tr><tr><td>Present weight (kg)</td><td>2965</td><td>5</td><td>9.1</td><td>15</td><td></td><td></td><td>21</td><td>35</td><td>41</td></tr><tr><td>Present height (cm)</td><td>55</td><td>68</td><td>82</td><td>100</td><td></td><td>103</td><td>120</td><td>131</td><td></td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td colspan="10"><bold>Development</bold></td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td>Degree of delay</td><td>n.a.</td><td>Sev</td><td>Sev</td><td>Mod</td><td>Mod-Sev</td><td>Mod</td><td>Mod</td><td>Sev</td><td>Sev</td></tr><tr><td>First words (mths)</td><td>n.a.</td><td>n.a.</td><td>-</td><td>-</td><td></td><td>60</td><td>36</td><td>None</td><td>None</td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td colspan="10"><bold>Neurology</bold></td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td>High tone</td><td>-</td><td>-</td><td>-</td><td>-</td><td></td><td>-</td><td>-</td><td>N/A</td><td>N/A</td></tr><tr><td>Brain MRI</td><td>dilated ventricles</td><td>pachygyria, hypoplasia callosal body</td><td>CTscan: N</td><td>hypoplasia callosal body</td><td></td><td>N/A</td><td>N/A</td><td>N/A</td><td>N/A</td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td colspan="10"><bold>Craniofacial features</bold></td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td>High forehead</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Proptosis</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Underdeveloped midface</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>-</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Short nose</td><td>+</td><td>+</td><td>+</td><td>+</td><td>-</td><td>-</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Prominent premaxilla</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Everted lips</td><td>-</td><td>-</td><td>-</td><td>+</td><td>+</td><td>-</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Gum hypertrophy</td><td>-</td><td>+</td><td>+</td><td>+</td><td></td><td>-</td><td>+</td><td>-</td><td>-</td></tr><tr><td>Retrognathia</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>-</td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td colspan="10"><bold>Eyes</bold></td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td>Myopia</td><td>-</td><td>-</td><td>-</td><td>−14</td><td>−5/-8</td><td>−12/-9</td><td>-</td><td>-</td><td>-</td></tr><tr><td>Blue sclerae</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>-</td><td>+</td><td>+</td><td>+</td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td colspan="10"><bold>Respiratory</bold></td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td>Choanal stenosis</td><td>-</td><td>+</td><td>-</td><td>-</td><td></td><td>-</td><td>+</td><td>-</td><td>-</td></tr><tr><td>Respiratory problems</td><td>+</td><td>+</td><td>-</td><td>+</td><td>+</td><td>-</td><td>+</td><td>-</td><td>+</td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td colspan="10"><bold>Musculo-Skeletal</bold></td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td>Abnormal bone maturation</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Bone fractures</td><td>-</td><td>-</td><td>-</td><td>1</td><td>-</td><td>-</td><td>4</td><td>-</td><td>-</td></tr><tr><td>Scoliosis</td><td>-</td><td>-</td><td>-</td><td>-</td><td>+</td><td>-</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Kyphosis</td><td>-</td><td>-</td><td>-</td><td>-</td><td>+</td><td>+</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Umbilical hernia</td><td>-</td><td>+</td><td>-</td><td>-</td><td></td><td>-</td><td>+</td><td>-</td><td>-</td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td colspan="10"><bold>Other</bold></td></tr><tr><td colspan="10"><hr></hr></td></tr><tr><td>Cardiac defect</td><td>-</td><td>-</td><td>-</td><td>-</td><td></td><td>VSD</td><td>-</td><td>VSD</td><td>-</td></tr><tr><td>Hearing loss</td><td>+</td><td>+</td><td>-</td><td>+</td><td></td><td>-</td><td>+</td><td>N/A</td><td>N/A</td></tr><tr><td>Hypertrichosis</td><td>-</td><td>+</td><td>+</td><td>+</td><td></td><td>+</td><td>+</td><td>+</td><td>+</td></tr><tr><td>Miscellaneous</td><td></td><td>IgA deficiency; vesico-ureteral reflux; long fingers</td><td>abnormal pinnae</td><td>hypospadias; glaucoma</td><td>long fingers</td><td></td><td>pyloric stenosis</td><td>Wilms tumor aged 4</td><td></td></tr></tbody></table><table-wrap-foot><fn><p>Abbreviations: M, male; F, female; n.a., not applicable; N/A, not available; sev, severe; mod, moderate; VSD, ventricular septal defect.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn1"><label>a</label><p>Deceased.</p></fn></table-wrap-foot></table-wrap></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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