A novel large deletion of the ICR1 region including H19 and putative enhancer elements
Identifieur interne : 000A32 ( Pmc/Curation ); précédent : 000A31; suivant : 000A33A novel large deletion of the ICR1 region including H19 and putative enhancer elements
Auteurs : Helen Fryssira ; Stella Amenta [Grèce] ; Deniz Kanber [Allemagne] ; Christalena Sofocleous ; Evangelia Lykopoulou [Grèce] ; Christina Kanaka-Gantenbein [Grèce] ; Flavia Cerrato [Italie] ; Hermann-Josef Lüdecke [Allemagne] ; Susanne Bens [Allemagne] ; Andrea Riccio [Italie] ; Karin Buiting [Allemagne]Source :
- BMC Medical Genetics [ 1471-2350 ] ; 2015.
Abstract
Beckwith-Wiedemann syndrome (BWS) is a rare pediatric overgrowth disorder with a variable clinical phenotype caused by deregulation affecting imprinted genes in the chromosomal region 11p15. Alterations of the imprinting control region 1 (ICR1) at the
A male patient was born with hypotonia, facial dysmorphisms and hypoglycemia suggestive of Beckwith-Wiedemann syndrome. Using methylation-specific (MS)-MLPA (Multiplex ligation-dependent probe amplification) we have identified a maternally inherited large deletion of the ICR1 region in a patient and his mother. The deletion results in a variable clinical expression with a classical BWS in the mother and a more severe presentation of BWS in her son. By genome-wide SNP array analysis the deletion was found to span ~100 kb genomic DNA including the ICR1DMR,
We here report on a novel large familial deletion of the ICR1 region in a BWS family. Due to the deletion of the ICR1-DMR CTCF binding cannot take place and the residual enhancer elements have access to the
The online version of this article (doi:10.1186/s12881-015-0173-2) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s12881-015-0173-2
PubMed: 25943194
PubMed Central: 4630834
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Helen Fryssira<affiliation><nlm:aff id="Aff1">Aghia Sophia Children’s Hospital, University of Athens Medical School, Athens, Goudi 11527 Greece</nlm:aff>
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</affiliation>
<affiliation><nlm:aff id="Aff1">Aghia Sophia Children’s Hospital, University of Athens Medical School, Athens, Goudi 11527 Greece</nlm:aff>
<wicri:noCountry code="subfield">Goudi 11527 Greece</wicri:noCountry>
</affiliation>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A novel large deletion of the ICR1 region including <italic>H19</italic>
and putative enhancer elements</title>
<author><name sortKey="Fryssira, Helen" sort="Fryssira, Helen" uniqKey="Fryssira H" first="Helen" last="Fryssira">Helen Fryssira</name>
<affiliation><nlm:aff id="Aff1">Aghia Sophia Children’s Hospital, University of Athens Medical School, Athens, Goudi 11527 Greece</nlm:aff>
<wicri:noCountry code="subfield">Goudi 11527 Greece</wicri:noCountry>
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<author><name sortKey="Amenta, Stella" sort="Amenta, Stella" uniqKey="Amenta S" first="Stella" last="Amenta">Stella Amenta</name>
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<country xml:lang="fr">Grèce</country>
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<author><name sortKey="Kanber, Deniz" sort="Kanber, Deniz" uniqKey="Kanber D" first="Deniz" last="Kanber">Deniz Kanber</name>
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<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen</wicri:regionArea>
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<author><name sortKey="Sofocleous, Christalena" sort="Sofocleous, Christalena" uniqKey="Sofocleous C" first="Christalena" last="Sofocleous">Christalena Sofocleous</name>
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<author><name sortKey="Lykopoulou, Evangelia" sort="Lykopoulou, Evangelia" uniqKey="Lykopoulou E" first="Evangelia" last="Lykopoulou">Evangelia Lykopoulou</name>
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<author><name sortKey="Kanaka Gantenbein, Christina" sort="Kanaka Gantenbein, Christina" uniqKey="Kanaka Gantenbein C" first="Christina" last="Kanaka-Gantenbein">Christina Kanaka-Gantenbein</name>
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<author><name sortKey="Cerrato, Flavia" sort="Cerrato, Flavia" uniqKey="Cerrato F" first="Flavia" last="Cerrato">Flavia Cerrato</name>
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<author><name sortKey="Ludecke, Hermann Josef" sort="Ludecke, Hermann Josef" uniqKey="Ludecke H" first="Hermann-Josef" last="Lüdecke">Hermann-Josef Lüdecke</name>
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<author><name sortKey="Bens, Susanne" sort="Bens, Susanne" uniqKey="Bens S" first="Susanne" last="Bens">Susanne Bens</name>
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<author><name sortKey="Riccio, Andrea" sort="Riccio, Andrea" uniqKey="Riccio A" first="Andrea" last="Riccio">Andrea Riccio</name>
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<country xml:lang="fr">Italie</country>
<wicri:regionArea>Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, DiSTABiF, 2nd University of Naples, Naples</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Buiting, Karin" sort="Buiting, Karin" uniqKey="Buiting K" first="Karin" last="Buiting">Karin Buiting</name>
<affiliation wicri:level="1"><nlm:aff id="Aff3">Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany</nlm:aff>
<country xml:lang="fr">Allemagne</country>
<wicri:regionArea>Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen</wicri:regionArea>
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<series><title level="j">BMC Medical Genetics</title>
<idno type="eISSN">1471-2350</idno>
<imprint><date when="2015">2015</date>
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<front><div type="abstract" xml:lang="en"><sec><title>Background</title>
<p>Beckwith-Wiedemann syndrome (BWS) is a rare pediatric overgrowth disorder with a variable clinical phenotype caused by deregulation affecting imprinted genes in the chromosomal region 11p15. Alterations of the imprinting control region 1 (ICR1) at the <italic>IGF2/H19</italic>
locus resulting in biallelic expression of <italic>IGF2</italic>
and biallelic silencing of <italic>H19</italic>
account for approximately 10% of patients with BWS. The majority of these patients have epimutations of the ICR1 without detectable DNA sequence changes. Only a few patients were found to have deletions. Most of these deletions are small affecting different parts of the ICR1 differentially methylated region (ICR1-DMR) removing target sequences for CTCF. Only a very few deletions reported so far include the <italic>H19</italic>
gene in addition to the CTCF binding sites. None of these deletions include <italic>IGF2</italic>
.</p>
</sec>
<sec><title>Case presentation</title>
<p>A male patient was born with hypotonia, facial dysmorphisms and hypoglycemia suggestive of Beckwith-Wiedemann syndrome. Using methylation-specific (MS)-MLPA (Multiplex ligation-dependent probe amplification) we have identified a maternally inherited large deletion of the ICR1 region in a patient and his mother. The deletion results in a variable clinical expression with a classical BWS in the mother and a more severe presentation of BWS in her son. By genome-wide SNP array analysis the deletion was found to span ~100 kb genomic DNA including the ICR1DMR, <italic>H19</italic>
, two adjacent non-imprinted genes and two of three predicted enhancer elements downstream to <italic>H19</italic>
. Methylation analysis by deep bisulfite next generation sequencing revealed hypermethylation of the maternal allele at the <italic>IGF2</italic>
locus in both, mother and child, although <italic>IGF2</italic>
is not affected by the deletion.</p>
</sec>
<sec><title>Conclusions</title>
<p>We here report on a novel large familial deletion of the ICR1 region in a BWS family. Due to the deletion of the ICR1-DMR CTCF binding cannot take place and the residual enhancer elements have access to the <italic>IGF2</italic>
promoters. The aberrant methylation (hypermethylation) of the maternal <italic>IGF2</italic>
allele in both affected family members may reflect the active state of the normally silenced maternal <italic>IGF2</italic>
copy and can be a consequence of the deletion. The deletion results in a variable clinical phenotype and expression.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (doi:10.1186/s12881-015-0173-2) contains supplementary material, which is available to authorized users.</p>
</sec>
</div>
</front>
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</TEI>
<pmc article-type="case-report"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">BMC Med Genet</journal-id>
<journal-id journal-id-type="iso-abbrev">BMC Med. Genet</journal-id>
<journal-title-group><journal-title>BMC Medical Genetics</journal-title>
</journal-title-group>
<issn pub-type="epub">1471-2350</issn>
<publisher><publisher-name>BioMed Central</publisher-name>
<publisher-loc>London</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25943194</article-id>
<article-id pub-id-type="pmc">4630834</article-id>
<article-id pub-id-type="publisher-id">173</article-id>
<article-id pub-id-type="doi">10.1186/s12881-015-0173-2</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Case Report</subject>
</subj-group>
</article-categories>
<title-group><article-title>A novel large deletion of the ICR1 region including <italic>H19</italic>
and putative enhancer elements</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Fryssira</surname>
<given-names>Helen</given-names>
</name>
<address><email>efrysira@yahoo.gr</email>
</address>
<xref ref-type="aff" rid="Aff1"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Amenta</surname>
<given-names>Stella</given-names>
</name>
<address><email>amenta@hol.gr</email>
</address>
<xref ref-type="aff" rid="Aff2"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kanber</surname>
<given-names>Deniz</given-names>
</name>
<address><email>deniz.kanber@uni-due.de</email>
</address>
<xref ref-type="aff" rid="Aff3"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sofocleous</surname>
<given-names>Christalena</given-names>
</name>
<address><email>csofokl@med.uoa.gr</email>
</address>
<xref ref-type="aff" rid="Aff1"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lykopoulou</surname>
<given-names>Evangelia</given-names>
</name>
<address><email>lilialykopoulou@gmail.com</email>
</address>
<xref ref-type="aff" rid="Aff4"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kanaka-Gantenbein</surname>
<given-names>Christina</given-names>
</name>
<address><email>c.kanaka-gantenbein@med.uoa.gr</email>
</address>
<xref ref-type="aff" rid="Aff4"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Cerrato</surname>
<given-names>Flavia</given-names>
</name>
<address><email>flavia.cerrato@unima2.it</email>
</address>
<xref ref-type="aff" rid="Aff5"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lüdecke</surname>
<given-names>Hermann-Josef</given-names>
</name>
<address><email>Hermann-josef.luedecke@uni-due.de</email>
</address>
<xref ref-type="aff" rid="Aff3"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bens</surname>
<given-names>Susanne</given-names>
</name>
<address><email>sbens@medgen.uni-kiel.de</email>
</address>
<xref ref-type="aff" rid="Aff6"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Riccio</surname>
<given-names>Andrea</given-names>
</name>
<address><email>andrea.riccio@unima2.it</email>
</address>
<xref ref-type="aff" rid="Aff5"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Buiting</surname>
<given-names>Karin</given-names>
</name>
<address><email>Karin.buiting@uni-due.de</email>
</address>
<xref ref-type="aff" rid="Aff3"></xref>
</contrib>
<aff id="Aff1"><label></label>
Aghia Sophia Children’s Hospital, University of Athens Medical School, Athens, Goudi 11527 Greece</aff>
<aff id="Aff2"><label></label>
Mitera Maternity Hospital, Athens, Greece</aff>
<aff id="Aff3"><label></label>
Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany</aff>
<aff id="Aff4"><label></label>
First Pediatric Clinic, Aghia Sophia” Children’s Hospital, University of Athens School of Medicine, Athens, Greece</aff>
<aff id="Aff5"><label></label>
Institute of Genetics and Biophysics A. Buzzati-Traverso, CNR, DiSTABiF, 2nd University of Naples, Naples, Italy</aff>
<aff id="Aff6"><label></label>
Institute of Human Genetics, University Hospital Schleswig-Hostein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany</aff>
</contrib-group>
<pub-date pub-type="epub"><day>6</day>
<month>5</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>6</day>
<month>5</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><year>2015</year>
</pub-date>
<volume>16</volume>
<elocation-id>30</elocation-id>
<history><date date-type="received"><day>9</day>
<month>11</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>22</day>
<month>4</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>© Fryssira et al.; licensee BioMed Central. 2015</copyright-statement>
<license license-type="open-access"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0">http://creativecommons.org/licenses/by/4.0</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>
) applies to the data made available in this article, unless otherwise stated.</license-p>
</license>
</permissions>
<abstract id="Abs1"><sec><title>Background</title>
<p>Beckwith-Wiedemann syndrome (BWS) is a rare pediatric overgrowth disorder with a variable clinical phenotype caused by deregulation affecting imprinted genes in the chromosomal region 11p15. Alterations of the imprinting control region 1 (ICR1) at the <italic>IGF2/H19</italic>
locus resulting in biallelic expression of <italic>IGF2</italic>
and biallelic silencing of <italic>H19</italic>
account for approximately 10% of patients with BWS. The majority of these patients have epimutations of the ICR1 without detectable DNA sequence changes. Only a few patients were found to have deletions. Most of these deletions are small affecting different parts of the ICR1 differentially methylated region (ICR1-DMR) removing target sequences for CTCF. Only a very few deletions reported so far include the <italic>H19</italic>
gene in addition to the CTCF binding sites. None of these deletions include <italic>IGF2</italic>
.</p>
</sec>
<sec><title>Case presentation</title>
<p>A male patient was born with hypotonia, facial dysmorphisms and hypoglycemia suggestive of Beckwith-Wiedemann syndrome. Using methylation-specific (MS)-MLPA (Multiplex ligation-dependent probe amplification) we have identified a maternally inherited large deletion of the ICR1 region in a patient and his mother. The deletion results in a variable clinical expression with a classical BWS in the mother and a more severe presentation of BWS in her son. By genome-wide SNP array analysis the deletion was found to span ~100 kb genomic DNA including the ICR1DMR, <italic>H19</italic>
, two adjacent non-imprinted genes and two of three predicted enhancer elements downstream to <italic>H19</italic>
. Methylation analysis by deep bisulfite next generation sequencing revealed hypermethylation of the maternal allele at the <italic>IGF2</italic>
locus in both, mother and child, although <italic>IGF2</italic>
is not affected by the deletion.</p>
</sec>
<sec><title>Conclusions</title>
<p>We here report on a novel large familial deletion of the ICR1 region in a BWS family. Due to the deletion of the ICR1-DMR CTCF binding cannot take place and the residual enhancer elements have access to the <italic>IGF2</italic>
promoters. The aberrant methylation (hypermethylation) of the maternal <italic>IGF2</italic>
allele in both affected family members may reflect the active state of the normally silenced maternal <italic>IGF2</italic>
copy and can be a consequence of the deletion. The deletion results in a variable clinical phenotype and expression.</p>
</sec>
<sec><title>Electronic supplementary material</title>
<p>The online version of this article (doi:10.1186/s12881-015-0173-2) contains supplementary material, which is available to authorized users.</p>
</sec>
</abstract>
<kwd-group xml:lang="en"><title>Keywords</title>
<kwd>Beckwith-Wiedemann syndrome</kwd>
<kwd>Genomic imprinting</kwd>
<kwd>Imprinting disorders</kwd>
<kwd>DNA methylation</kwd>
</kwd-group>
<custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name>
<meta-value>© The Author(s) 2015</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
</front>
</pmc>
</record>
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