Systematic analysis of copy number variants of a large cohort of orofacial cleft patients identifies candidate genes for orofacial clefts
Identifieur interne : 001783 ( Main/Exploration ); précédent : 001782; suivant : 001784Systematic analysis of copy number variants of a large cohort of orofacial cleft patients identifies candidate genes for orofacial clefts
Auteurs : Federica Conte [Pays-Bas, Italie] ; Martin Oti [Pays-Bas] ; Jill Dixon [Royaume-Uni] ; Carine E. L. Carels [Pays-Bas] ; Michele Rubini [Italie] ; Huiqing Zhou [Pays-Bas]Source :
- Human Genetics [ 0340-6717 ] ; 2015.
Abstract
Orofacial clefts (OFCs) represent a large fraction of human birth defects and are one of the most common phenotypes affected by large copy number variants (CNVs). Due to the limited number of CNV patients in individual centers, CNV analyses of a large number of OFC patients are challenging. The present study analyzed 249 genomic deletions and 226 duplications from a cohort of 312 OFC patients reported in two publicly accessible databases of chromosome imbalance and phenotype in humans, DECIPHER and ECARUCA. Genomic regions deleted or duplicated in multiple patients were identified, and genes in these overlapping CNVs were prioritized based on the number of genes encompassed by the region and gene expression in embryonic mouse palate. Our analyses of these overlapping CNVs identified two genes known to be causative for human OFCs,
The online version of this article (doi:10.1007/s00439-015-1606-x) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1007/s00439-015-1606-x
PubMed: 26561393
PubMed Central: 4698300
Affiliations:
- Italie, Pays-Bas, Royaume-Uni
- Angleterre, Grand Manchester, Gueldre
- Manchester, Nimègue
- Université de Manchester
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Radboud University, Nijmegen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff2">Medical Genetic Unit, Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Genetic Unit, Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara</wicri:regionArea><wicri:noRegion>Ferrara</wicri:noRegion></affiliation></author><author><name sortKey="Oti, Martin" sort="Oti, Martin" uniqKey="Oti M" first="Martin" last="Oti">Martin Oti</name><affiliation wicri:level="3"><nlm:aff id="Aff1">Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Dixon, Jill" sort="Dixon, Jill" uniqKey="Dixon J" first="Jill" last="Dixon">Jill Dixon</name><affiliation wicri:level="4"><nlm:aff id="Aff3">Faculty of Medical and Human Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT UK</nlm:aff><orgName type="university">Université de Manchester</orgName><country>Royaume-Uni</country><placeName><settlement type="city">Manchester</settlement><region type="nation">Angleterre</region><region nuts="2" type="region">Grand Manchester</region></placeName></affiliation></author><author><name sortKey="Carels, Carine E L" sort="Carels, Carine E L" uniqKey="Carels C" first="Carine E. 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Carels</name><affiliation wicri:level="3"><nlm:aff id="Aff4">Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author><author><name sortKey="Rubini, Michele" sort="Rubini, Michele" uniqKey="Rubini M" first="Michele" last="Rubini">Michele Rubini</name><affiliation wicri:level="1"><nlm:aff id="Aff2">Medical Genetic Unit, Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Genetic Unit, Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, Ferrara</wicri:regionArea><wicri:noRegion>Ferrara</wicri:noRegion></affiliation></author><author><name sortKey="Zhou, Huiqing" sort="Zhou, Huiqing" uniqKey="Zhou H" first="Huiqing" last="Zhou">Huiqing Zhou</name><affiliation wicri:level="3"><nlm:aff id="Aff1">Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation><affiliation wicri:level="3"><nlm:aff id="Aff5">Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands</nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen</wicri:regionArea><placeName><settlement type="city">Nimègue</settlement><region type="province" nuts="2">Gueldre</region></placeName></affiliation></author></analytic><series><title level="j">Human Genetics</title><idno type="ISSN">0340-6717</idno><idno type="eISSN">1432-1203</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Orofacial clefts (OFCs) represent a large fraction of human birth defects and are one of the most common phenotypes affected by large copy number variants (CNVs). Due to the limited number of CNV patients in individual centers, CNV analyses of a large number of OFC patients are challenging. The present study analyzed 249 genomic deletions and 226 duplications from a cohort of 312 OFC patients reported in two publicly accessible databases of chromosome imbalance and phenotype in humans, DECIPHER and ECARUCA. Genomic regions deleted or duplicated in multiple patients were identified, and genes in these overlapping CNVs were prioritized based on the number of genes encompassed by the region and gene expression in embryonic mouse palate. Our analyses of these overlapping CNVs identified two genes known to be causative for human OFCs, <italic>SATB2</italic> and <italic>MEIS2,</italic> and 12 genes (<italic>DGCR6, FGF2, FRZB, LETM1</italic>, <italic>MAPK3</italic>, <italic>SPRY1</italic>, <italic>THBS1, TSHZ1, TTC28, TULP4, WHSC1, WHSC2</italic>) that are associated with OFC or orofacial development. Additionally, we report 34 deleted and 24 duplicated genes that have not previously been associated with OFCs but are associated with the BMP, MAPK and RAC1 pathways. Statistical analyses show that the high number of overlapping CNVs is not due to random occurrence. The identified genes are not located in highly variable genomic regions in healthy populations and are significantly enriched for genes that are involved in orofacial development. In summary, we report a CNV analysis pipeline of a large cohort of OFC patients and identify novel candidate OFC genes.</p><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1007/s00439-015-1606-x) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Abel, El" uniqKey="Abel E">EL Abel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Abrishamchian, Ar" uniqKey="Abrishamchian A">AR Abrishamchian</name></author><author><name sortKey="Khoury, Mj" uniqKey="Khoury M">MJ Khoury</name></author><author><name sortKey="Calle, Ee" uniqKey="Calle E">EE Calle</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Adams, Jc" uniqKey="Adams J">JC Adams</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Adams, Jc" uniqKey="Adams 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Naranjo</name></author><author><name sortKey="Francis West, P" uniqKey="Francis West P">P Francis-West</name></author><author><name sortKey="Altherr, Mr" uniqKey="Altherr M">MR Altherr</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wyszynski, Df" uniqKey="Wyszynski D">DF Wyszynski</name></author><author><name sortKey="Beaty, Th" uniqKey="Beaty T">TH Beaty</name></author><author><name sortKey="Maestri, Ne" uniqKey="Maestri N">NE Maestri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yagi, H" uniqKey="Yagi H">H Yagi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yamamoto, T" uniqKey="Yamamoto T">T Yamamoto</name></author><author><name sortKey="Cui, Xm" uniqKey="Cui X">XM Cui</name></author><author><name sortKey="Shuler, Cf" uniqKey="Shuler C">CF Shuler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, X" uniqKey="Yang X">X Yang</name></author><author><name sortKey="Kilgallen, S" uniqKey="Kilgallen S">S Kilgallen</name></author><author><name sortKey="Andreeva, V" uniqKey="Andreeva V">V Andreeva</name></author><author><name sortKey="Spicer, Db" uniqKey="Spicer D">DB Spicer</name></author><author><name sortKey="Pinz, I" uniqKey="Pinz I">I Pinz</name></author><author><name sortKey="Friesel, R" uniqKey="Friesel R">R Friesel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yigzaw, Y" uniqKey="Yigzaw Y">Y Yigzaw</name></author><author><name sortKey="Cartin, L" uniqKey="Cartin L">L Cartin</name></author><author><name sortKey="Pierre, S" uniqKey="Pierre S">S Pierre</name></author><author><name sortKey="Scholich, K" uniqKey="Scholich K">K Scholich</name></author><author><name sortKey="Patel, Tb" uniqKey="Patel T">TB Patel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, Z" uniqKey="Zhang Z">Z Zhang</name></author><author><name sortKey="Song, Y" uniqKey="Song Y">Y Song</name></author><author><name sortKey="Zhao, X" uniqKey="Zhao X">X Zhao</name></author><author><name sortKey="Zhang, X" uniqKey="Zhang X">X Zhang</name></author><author><name sortKey="Fermin, C" uniqKey="Fermin C">C Fermin</name></author><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhao, G" uniqKey="Zhao G">G Zhao</name></author><author><name sortKey="Wojciechowski, Mc" uniqKey="Wojciechowski M">MC Wojciechowski</name></author><author><name sortKey="Jee, S" uniqKey="Jee S">S Jee</name></author><author><name sortKey="Boros, J" uniqKey="Boros J">J Boros</name></author><author><name sortKey="Mcavoy, Jw" uniqKey="Mcavoy J">JW McAvoy</name></author><author><name sortKey="Lovicu, Fj" uniqKey="Lovicu F">FJ Lovicu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zollino, M" uniqKey="Zollino M">M Zollino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zollino, M" uniqKey="Zollino M">M Zollino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zucchero, Tm" uniqKey="Zucchero T">TM Zucchero</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Italie</li><li>Pays-Bas</li><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Grand Manchester</li><li>Gueldre</li></region><settlement><li>Manchester</li><li>Nimègue</li></settlement><orgName><li>Université de Manchester</li></orgName></list><tree><country name="Pays-Bas"><region name="Gueldre"><name sortKey="Conte, Federica" sort="Conte, Federica" uniqKey="Conte F" first="Federica" last="Conte">Federica Conte</name></region><name sortKey="Carels, Carine E L" sort="Carels, Carine E L" uniqKey="Carels C" first="Carine E. L." last="Carels">Carine E. L. Carels</name><name sortKey="Oti, Martin" sort="Oti, Martin" uniqKey="Oti M" first="Martin" last="Oti">Martin Oti</name><name sortKey="Zhou, Huiqing" sort="Zhou, Huiqing" uniqKey="Zhou H" first="Huiqing" last="Zhou">Huiqing Zhou</name><name sortKey="Zhou, Huiqing" sort="Zhou, Huiqing" uniqKey="Zhou H" first="Huiqing" last="Zhou">Huiqing Zhou</name></country><country name="Italie"><noRegion><name sortKey="Conte, Federica" sort="Conte, Federica" uniqKey="Conte F" first="Federica" last="Conte">Federica Conte</name></noRegion><name sortKey="Rubini, Michele" sort="Rubini, Michele" uniqKey="Rubini M" first="Michele" last="Rubini">Michele Rubini</name></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Dixon, Jill" sort="Dixon, Jill" uniqKey="Dixon J" first="Jill" last="Dixon">Jill Dixon</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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