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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Contribution of Global Rare Copy-Number Variants to the Risk of Sporadic Congenital Heart Disease</title><author><name sortKey="Soemedi, Rachel" sort="Soemedi, Rachel" uniqKey="Soemedi R" first="Rachel" last="Soemedi">Rachel Soemedi</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Wilson, Ian J" sort="Wilson, Ian J" uniqKey="Wilson I" first="Ian J." last="Wilson">Ian J. Wilson</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Bentham, Jamie" sort="Bentham, Jamie" uniqKey="Bentham J" first="Jamie" last="Bentham">Jamie Bentham</name><affiliation><nlm:aff id="aff2">Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK</nlm:aff></affiliation></author><author><name sortKey="Darlay, Rebecca" sort="Darlay, Rebecca" uniqKey="Darlay R" first="Rebecca" last="Darlay">Rebecca Darlay</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Topf, Ana" sort="Topf, Ana" uniqKey="Topf A" first="Ana" last="Töpf">Ana Töpf</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Zelenika, Diana" sort="Zelenika, Diana" uniqKey="Zelenika D" first="Diana" last="Zelenika">Diana Zelenika</name><affiliation><nlm:aff id="aff3">Commissariat à l’Energie Atomique, Centre National de Génotypage, 91057 Evry Cedex, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Ceph Fondation Jean Dausset, 75010 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Cosgrove, Catherine" sort="Cosgrove, Catherine" uniqKey="Cosgrove C" first="Catherine" last="Cosgrove">Catherine Cosgrove</name><affiliation><nlm:aff id="aff2">Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK</nlm:aff></affiliation></author><author><name sortKey="Setchfield, Kerry" sort="Setchfield, Kerry" uniqKey="Setchfield K" first="Kerry" last="Setchfield">Kerry Setchfield</name><affiliation><nlm:aff id="aff5">School of Biology, University of Nottingham, Nottingham, NG7 2UH, UK</nlm:aff></affiliation></author><author><name sortKey="Thornborough, Chris" sort="Thornborough, Chris" uniqKey="Thornborough C" first="Chris" last="Thornborough">Chris Thornborough</name><affiliation><nlm:aff id="aff6">East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester LE3 9QP, UK</nlm:aff></affiliation></author><author><name sortKey="Granados Riveron, Javier" sort="Granados Riveron, Javier" uniqKey="Granados Riveron J" first="Javier" last="Granados-Riveron">Javier Granados-Riveron</name><affiliation><nlm:aff id="aff5">School of Biology, University of Nottingham, Nottingham, NG7 2UH, UK</nlm:aff></affiliation></author><author><name sortKey="Blue, Gillian M" sort="Blue, Gillian M" uniqKey="Blue G" first="Gillian M." last="Blue">Gillian M. Blue</name><affiliation><nlm:aff id="aff7">Heart Centre for Children, The Children’s Hospital at Westmead, Sydney NSW 2145, Australia</nlm:aff></affiliation></author><author><name sortKey="Breckpot, Jeroen" sort="Breckpot, Jeroen" uniqKey="Breckpot J" first="Jeroen" last="Breckpot">Jeroen Breckpot</name><affiliation><nlm:aff id="aff8">Centre for Human Genetics, University Hospital Leuven, Leuven B-3000, Belgium</nlm:aff></affiliation></author><author><name sortKey="Hellens, Stephen" sort="Hellens, Stephen" uniqKey="Hellens S" first="Stephen" last="Hellens">Stephen Hellens</name><affiliation><nlm:aff id="aff9">Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Zwolinkski, Simon" sort="Zwolinkski, Simon" uniqKey="Zwolinkski S" first="Simon" last="Zwolinkski">Simon Zwolinkski</name><affiliation><nlm:aff id="aff9">Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Glen, Elise" sort="Glen, Elise" uniqKey="Glen E" first="Elise" last="Glen">Elise Glen</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Mamasoula, Chrysovalanto" sort="Mamasoula, Chrysovalanto" uniqKey="Mamasoula C" first="Chrysovalanto" last="Mamasoula">Chrysovalanto Mamasoula</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Rahman, Thahira J" sort="Rahman, Thahira J" uniqKey="Rahman T" first="Thahira J." last="Rahman">Thahira J. Rahman</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Hall, Darroch" sort="Hall, Darroch" uniqKey="Hall D" first="Darroch" last="Hall">Darroch Hall</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Rauch, Anita" sort="Rauch, Anita" uniqKey="Rauch A" first="Anita" last="Rauch">Anita Rauch</name><affiliation><nlm:aff id="aff10">Institute of Medical Genetics, University of Zurich, Zurich-Schwerzenbach CH-8603, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Devriendt, Koenraad" sort="Devriendt, Koenraad" uniqKey="Devriendt K" first="Koenraad" last="Devriendt">Koenraad Devriendt</name><affiliation><nlm:aff id="aff8">Centre for Human Genetics, University Hospital Leuven, Leuven B-3000, Belgium</nlm:aff></affiliation></author><author><name sortKey="Gewillig, Marc" sort="Gewillig, Marc" uniqKey="Gewillig M" first="Marc" last="Gewillig">Marc Gewillig</name><affiliation><nlm:aff id="aff11">Paediatric Cardiology, University of Leuven, Leuven B-3000, Belgium</nlm:aff></affiliation></author><author><name sortKey="O Ullivan, John" sort="O Ullivan, John" uniqKey="O Ullivan J" first="John" last="O Ullivan">John O Ullivan</name><affiliation><nlm:aff id="aff12">Paediatric Cardiology, Newcastle upon Tyne Hospitals, National Health Service Foundation Trust, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK</nlm:aff></affiliation></author><author><name sortKey="Winlaw, David S" sort="Winlaw, David S" uniqKey="Winlaw D" first="David S." last="Winlaw">David S. Winlaw</name><affiliation><nlm:aff id="aff7">Heart Centre for Children, The Children’s Hospital at Westmead, Sydney NSW 2145, Australia</nlm:aff></affiliation></author><author><name sortKey="Bu Ock, Frances" sort="Bu Ock, Frances" uniqKey="Bu Ock F" first="Frances" last="Bu Ock">Frances Bu Ock</name><affiliation><nlm:aff id="aff6">East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester LE3 9QP, UK</nlm:aff></affiliation></author><author><name sortKey="Brook, J David" sort="Brook, J David" uniqKey="Brook J" first="J. David" last="Brook">J. David Brook</name><affiliation><nlm:aff id="aff5">School of Biology, University of Nottingham, Nottingham, NG7 2UH, UK</nlm:aff></affiliation></author><author><name sortKey="Bhattacharya, Shoumo" sort="Bhattacharya, Shoumo" uniqKey="Bhattacharya S" first="Shoumo" last="Bhattacharya">Shoumo Bhattacharya</name><affiliation><nlm:aff id="aff2">Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK</nlm:aff></affiliation></author><author><name sortKey="Lathrop, Mark" sort="Lathrop, Mark" uniqKey="Lathrop M" first="Mark" last="Lathrop">Mark Lathrop</name><affiliation><nlm:aff id="aff3">Commissariat à l’Energie Atomique, Centre National de Génotypage, 91057 Evry Cedex, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Ceph Fondation Jean Dausset, 75010 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Santibanez Koref, Mauro" sort="Santibanez Koref, Mauro" uniqKey="Santibanez Koref M" first="Mauro" last="Santibanez-Koref">Mauro Santibanez-Koref</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Cordell, Heather J" sort="Cordell, Heather J" uniqKey="Cordell H" first="Heather J." last="Cordell">Heather J. Cordell</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Goodship, Judith A" sort="Goodship, Judith A" uniqKey="Goodship J" first="Judith A." last="Goodship">Judith A. Goodship</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Keavney, Bernard D" sort="Keavney, Bernard D" uniqKey="Keavney B" first="Bernard D." last="Keavney">Bernard D. Keavney</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">22939634</idno><idno type="pmc">3511986</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511986</idno><idno type="RBID">PMC:3511986</idno><idno type="doi">10.1016/j.ajhg.2012.08.003</idno><date when="2012">2012</date><idno type="wicri:Area/Pmc/Corpus">001682</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001682</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Contribution of Global Rare Copy-Number Variants to the Risk of Sporadic Congenital Heart Disease</title><author><name sortKey="Soemedi, Rachel" sort="Soemedi, Rachel" uniqKey="Soemedi R" first="Rachel" last="Soemedi">Rachel Soemedi</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Wilson, Ian J" sort="Wilson, Ian J" uniqKey="Wilson I" first="Ian J." last="Wilson">Ian J. Wilson</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Bentham, Jamie" sort="Bentham, Jamie" uniqKey="Bentham J" first="Jamie" last="Bentham">Jamie Bentham</name><affiliation><nlm:aff id="aff2">Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK</nlm:aff></affiliation></author><author><name sortKey="Darlay, Rebecca" sort="Darlay, Rebecca" uniqKey="Darlay R" first="Rebecca" last="Darlay">Rebecca Darlay</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Topf, Ana" sort="Topf, Ana" uniqKey="Topf A" first="Ana" last="Töpf">Ana Töpf</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Zelenika, Diana" sort="Zelenika, Diana" uniqKey="Zelenika D" first="Diana" last="Zelenika">Diana Zelenika</name><affiliation><nlm:aff id="aff3">Commissariat à l’Energie Atomique, Centre National de Génotypage, 91057 Evry Cedex, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Ceph Fondation Jean Dausset, 75010 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Cosgrove, Catherine" sort="Cosgrove, Catherine" uniqKey="Cosgrove C" first="Catherine" last="Cosgrove">Catherine Cosgrove</name><affiliation><nlm:aff id="aff2">Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK</nlm:aff></affiliation></author><author><name sortKey="Setchfield, Kerry" sort="Setchfield, Kerry" uniqKey="Setchfield K" first="Kerry" last="Setchfield">Kerry Setchfield</name><affiliation><nlm:aff id="aff5">School of Biology, University of Nottingham, Nottingham, NG7 2UH, UK</nlm:aff></affiliation></author><author><name sortKey="Thornborough, Chris" sort="Thornborough, Chris" uniqKey="Thornborough C" first="Chris" last="Thornborough">Chris Thornborough</name><affiliation><nlm:aff id="aff6">East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester LE3 9QP, UK</nlm:aff></affiliation></author><author><name sortKey="Granados Riveron, Javier" sort="Granados Riveron, Javier" uniqKey="Granados Riveron J" first="Javier" last="Granados-Riveron">Javier Granados-Riveron</name><affiliation><nlm:aff id="aff5">School of Biology, University of Nottingham, Nottingham, NG7 2UH, UK</nlm:aff></affiliation></author><author><name sortKey="Blue, Gillian M" sort="Blue, Gillian M" uniqKey="Blue G" first="Gillian M." last="Blue">Gillian M. Blue</name><affiliation><nlm:aff id="aff7">Heart Centre for Children, The Children’s Hospital at Westmead, Sydney NSW 2145, Australia</nlm:aff></affiliation></author><author><name sortKey="Breckpot, Jeroen" sort="Breckpot, Jeroen" uniqKey="Breckpot J" first="Jeroen" last="Breckpot">Jeroen Breckpot</name><affiliation><nlm:aff id="aff8">Centre for Human Genetics, University Hospital Leuven, Leuven B-3000, Belgium</nlm:aff></affiliation></author><author><name sortKey="Hellens, Stephen" sort="Hellens, Stephen" uniqKey="Hellens S" first="Stephen" last="Hellens">Stephen Hellens</name><affiliation><nlm:aff id="aff9">Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Zwolinkski, Simon" sort="Zwolinkski, Simon" uniqKey="Zwolinkski S" first="Simon" last="Zwolinkski">Simon Zwolinkski</name><affiliation><nlm:aff id="aff9">Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Glen, Elise" sort="Glen, Elise" uniqKey="Glen E" first="Elise" last="Glen">Elise Glen</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Mamasoula, Chrysovalanto" sort="Mamasoula, Chrysovalanto" uniqKey="Mamasoula C" first="Chrysovalanto" last="Mamasoula">Chrysovalanto Mamasoula</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Rahman, Thahira J" sort="Rahman, Thahira J" uniqKey="Rahman T" first="Thahira J." last="Rahman">Thahira J. Rahman</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Hall, Darroch" sort="Hall, Darroch" uniqKey="Hall D" first="Darroch" last="Hall">Darroch Hall</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Rauch, Anita" sort="Rauch, Anita" uniqKey="Rauch A" first="Anita" last="Rauch">Anita Rauch</name><affiliation><nlm:aff id="aff10">Institute of Medical Genetics, University of Zurich, Zurich-Schwerzenbach CH-8603, Switzerland</nlm:aff></affiliation></author><author><name sortKey="Devriendt, Koenraad" sort="Devriendt, Koenraad" uniqKey="Devriendt K" first="Koenraad" last="Devriendt">Koenraad Devriendt</name><affiliation><nlm:aff id="aff8">Centre for Human Genetics, University Hospital Leuven, Leuven B-3000, Belgium</nlm:aff></affiliation></author><author><name sortKey="Gewillig, Marc" sort="Gewillig, Marc" uniqKey="Gewillig M" first="Marc" last="Gewillig">Marc Gewillig</name><affiliation><nlm:aff id="aff11">Paediatric Cardiology, University of Leuven, Leuven B-3000, Belgium</nlm:aff></affiliation></author><author><name sortKey="O Ullivan, John" sort="O Ullivan, John" uniqKey="O Ullivan J" first="John" last="O Ullivan">John O Ullivan</name><affiliation><nlm:aff id="aff12">Paediatric Cardiology, Newcastle upon Tyne Hospitals, National Health Service Foundation Trust, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK</nlm:aff></affiliation></author><author><name sortKey="Winlaw, David S" sort="Winlaw, David S" uniqKey="Winlaw D" first="David S." last="Winlaw">David S. Winlaw</name><affiliation><nlm:aff id="aff7">Heart Centre for Children, The Children’s Hospital at Westmead, Sydney NSW 2145, Australia</nlm:aff></affiliation></author><author><name sortKey="Bu Ock, Frances" sort="Bu Ock, Frances" uniqKey="Bu Ock F" first="Frances" last="Bu Ock">Frances Bu Ock</name><affiliation><nlm:aff id="aff6">East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester LE3 9QP, UK</nlm:aff></affiliation></author><author><name sortKey="Brook, J David" sort="Brook, J David" uniqKey="Brook J" first="J. David" last="Brook">J. David Brook</name><affiliation><nlm:aff id="aff5">School of Biology, University of Nottingham, Nottingham, NG7 2UH, UK</nlm:aff></affiliation></author><author><name sortKey="Bhattacharya, Shoumo" sort="Bhattacharya, Shoumo" uniqKey="Bhattacharya S" first="Shoumo" last="Bhattacharya">Shoumo Bhattacharya</name><affiliation><nlm:aff id="aff2">Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK</nlm:aff></affiliation></author><author><name sortKey="Lathrop, Mark" sort="Lathrop, Mark" uniqKey="Lathrop M" first="Mark" last="Lathrop">Mark Lathrop</name><affiliation><nlm:aff id="aff3">Commissariat à l’Energie Atomique, Centre National de Génotypage, 91057 Evry Cedex, France</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Ceph Fondation Jean Dausset, 75010 Paris, France</nlm:aff></affiliation></author><author><name sortKey="Santibanez Koref, Mauro" sort="Santibanez Koref, Mauro" uniqKey="Santibanez Koref M" first="Mauro" last="Santibanez-Koref">Mauro Santibanez-Koref</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Cordell, Heather J" sort="Cordell, Heather J" uniqKey="Cordell H" first="Heather J." last="Cordell">Heather J. Cordell</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Goodship, Judith A" sort="Goodship, Judith A" uniqKey="Goodship J" first="Judith A." last="Goodship">Judith A. Goodship</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</nlm:aff></affiliation></author><author><name sortKey="Keavney, Bernard D" sort="Keavney, Bernard D" uniqKey="Keavney B" first="Bernard D." last="Keavney">Bernard D. Keavney</name><affiliation><nlm:aff id="aff1">Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</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="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Previous studies have shown that copy-number variants (CNVs) contribute to the risk of complex developmental phenotypes. However, the contribution of global CNV burden to the risk of sporadic congenital heart disease (CHD) remains incompletely defined. We generated genome-wide CNV data by using Illumina 660W-Quad SNP arrays in 2,256 individuals with CHD, 283 trio CHD-affected families, and 1,538 controls. We found association of rare genic deletions with CHD risk (odds ratio [OR] = 1.8, p = 0.0008). Rare deletions in study participants with CHD had higher gene content (p = 0.001) with higher haploinsufficiency scores (p = 0.03) than they did in controls, and they were enriched with Wnt-signaling genes (p = 1 × 10<sup>−5</sup>). Recurrent 15q11.2 deletions were associated with CHD risk (OR = 8.2, p = 0.02). Rare de novo CNVs were observed in ∼5% of CHD trios; 10 out of 11 occurred on the paternally transmitted chromosome (p = 0.01). Some of the rare de novo CNVs spanned genes known to be involved in heart development (e.g., <italic>HAND2</italic> and <italic>GJA5</italic>). Rare genic deletions contribute ∼4% of the population-attributable risk of sporadic CHD. Second to previously described CNVs at 1q21.1, deletions at 15q11.2 and those implicating Wnt signaling are the most significant contributors to the risk of sporadic CHD. Rare de novo CNVs identified in CHD trios exhibit paternal origin bias.</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-id journal-id-type="iso-abbrev">Am. J. Hum. Genet</journal-id><journal-title-group><journal-title>American Journal of Human Genetics</journal-title></journal-title-group><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">22939634</article-id><article-id pub-id-type="pmc">3511986</article-id><article-id pub-id-type="publisher-id">AJHG1230</article-id><article-id pub-id-type="doi">10.1016/j.ajhg.2012.08.003</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Contribution of Global Rare Copy-Number Variants to the Risk of Sporadic Congenital Heart Disease</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Soemedi</surname><given-names>Rachel</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Wilson</surname><given-names>Ian J.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Bentham</surname><given-names>Jamie</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Darlay</surname><given-names>Rebecca</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Töpf</surname><given-names>Ana</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Zelenika</surname><given-names>Diana</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Cosgrove</surname><given-names>Catherine</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Setchfield</surname><given-names>Kerry</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Thornborough</surname><given-names>Chris</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Granados-Riveron</surname><given-names>Javier</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Blue</surname><given-names>Gillian M.</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Breckpot</surname><given-names>Jeroen</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Hellens</surname><given-names>Stephen</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Zwolinkski</surname><given-names>Simon</given-names></name><xref rid="aff9" ref-type="aff">9</xref></contrib><contrib contrib-type="author"><name><surname>Glen</surname><given-names>Elise</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Mamasoula</surname><given-names>Chrysovalanto</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Rahman</surname><given-names>Thahira J.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Hall</surname><given-names>Darroch</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Rauch</surname><given-names>Anita</given-names></name><xref rid="aff10" ref-type="aff">10</xref></contrib><contrib contrib-type="author"><name><surname>Devriendt</surname><given-names>Koenraad</given-names></name><xref rid="aff8" ref-type="aff">8</xref></contrib><contrib contrib-type="author"><name><surname>Gewillig</surname><given-names>Marc</given-names></name><xref rid="aff11" ref-type="aff">11</xref></contrib><contrib contrib-type="author"><name><surname>O’ Sullivan</surname><given-names>John</given-names></name><xref rid="aff12" ref-type="aff">12</xref></contrib><contrib contrib-type="author"><name><surname>Winlaw</surname><given-names>David S.</given-names></name><xref rid="aff7" ref-type="aff">7</xref></contrib><contrib contrib-type="author"><name><surname>Bu’Lock</surname><given-names>Frances</given-names></name><xref rid="aff6" ref-type="aff">6</xref></contrib><contrib contrib-type="author"><name><surname>Brook</surname><given-names>J. David</given-names></name><xref rid="aff5" ref-type="aff">5</xref></contrib><contrib contrib-type="author"><name><surname>Bhattacharya</surname><given-names>Shoumo</given-names></name><xref rid="aff2" ref-type="aff">2</xref></contrib><contrib contrib-type="author"><name><surname>Lathrop</surname><given-names>Mark</given-names></name><xref rid="aff3" ref-type="aff">3</xref><xref rid="aff4" ref-type="aff">4</xref></contrib><contrib contrib-type="author"><name><surname>Santibanez-Koref</surname><given-names>Mauro</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Cordell</surname><given-names>Heather J.</given-names></name><xref rid="aff1" ref-type="aff">1</xref></contrib><contrib contrib-type="author"><name><surname>Goodship</surname><given-names>Judith A.</given-names></name><email>j.a.goodship@newcastle.ac.uk</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib><contrib contrib-type="author"><name><surname>Keavney</surname><given-names>Bernard D.</given-names></name><email>b.d.keavney@newcastle.ac.uk</email><xref rid="aff1" ref-type="aff">1</xref><xref rid="cor2" ref-type="corresp">∗∗</xref></contrib></contrib-group><aff id="aff1"><label>1</label>Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK</aff><aff id="aff2"><label>2</label>Department of Cardiovascular Medicine and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK</aff><aff id="aff3"><label>3</label>Commissariat à l’Energie Atomique, Centre National de Génotypage, 91057 Evry Cedex, France</aff><aff id="aff4"><label>4</label>Ceph Fondation Jean Dausset, 75010 Paris, France</aff><aff id="aff5"><label>5</label>School of Biology, University of Nottingham, Nottingham, NG7 2UH, UK</aff><aff id="aff6"><label>6</label>East Midlands Congenital Heart Centre, Glenfield Hospital, Leicester LE3 9QP, UK</aff><aff id="aff7"><label>7</label>Heart Centre for Children, The Children’s Hospital at Westmead, Sydney NSW 2145, Australia</aff><aff id="aff8"><label>8</label>Centre for Human Genetics, University Hospital Leuven, Leuven B-3000, Belgium</aff><aff id="aff9"><label>9</label>Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne NE1 3BZ, UK</aff><aff id="aff10"><label>10</label>Institute of Medical Genetics, University of Zurich, Zurich-Schwerzenbach CH-8603, Switzerland</aff><aff id="aff11"><label>11</label>Paediatric Cardiology, University of Leuven, Leuven B-3000, Belgium</aff><aff id="aff12"><label>12</label>Paediatric Cardiology, Newcastle upon Tyne Hospitals, National Health Service Foundation Trust, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK</aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>j.a.goodship@newcastle.ac.uk</email></corresp><corresp id="cor2"><label>∗∗</label>Corresponding author <email>b.d.keavney@newcastle.ac.uk</email></corresp></author-notes><pub-date pub-type="ppub"><day>07</day><month>9</month><year>2012</year></pub-date><volume>91</volume><issue>3</issue><fpage>489</fpage><lpage>501</lpage><history><date date-type="received"><day>24</day><month>2</month><year>2012</year></date><date date-type="rev-recd"><day>25</day><month>4</month><year>2012</year></date><date date-type="accepted"><day>2</day><month>8</month><year>2012</year></date></history><permissions><copyright-statement>© 2012 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved.</copyright-statement><copyright-year>2012</copyright-year><copyright-holder>The American Society of Human Genetics</copyright-holder></permissions><abstract><p>Previous studies have shown that copy-number variants (CNVs) contribute to the risk of complex developmental phenotypes. However, the contribution of global CNV burden to the risk of sporadic congenital heart disease (CHD) remains incompletely defined. We generated genome-wide CNV data by using Illumina 660W-Quad SNP arrays in 2,256 individuals with CHD, 283 trio CHD-affected families, and 1,538 controls. We found association of rare genic deletions with CHD risk (odds ratio [OR] = 1.8, p = 0.0008). Rare deletions in study participants with CHD had higher gene content (p = 0.001) with higher haploinsufficiency scores (p = 0.03) than they did in controls, and they were enriched with Wnt-signaling genes (p = 1 × 10<sup>−5</sup>). Recurrent 15q11.2 deletions were associated with CHD risk (OR = 8.2, p = 0.02). Rare de novo CNVs were observed in ∼5% of CHD trios; 10 out of 11 occurred on the paternally transmitted chromosome (p = 0.01). Some of the rare de novo CNVs spanned genes known to be involved in heart development (e.g., <italic>HAND2</italic> and <italic>GJA5</italic>). Rare genic deletions contribute ∼4% of the population-attributable risk of sporadic CHD. Second to previously described CNVs at 1q21.1, deletions at 15q11.2 and those implicating Wnt signaling are the most significant contributors to the risk of sporadic CHD. Rare de novo CNVs identified in CHD trios exhibit paternal origin bias.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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