Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability
Abstract Background Tissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders. Methods Two pediatric patients with global developmental delay and intellectual disability phenotype underwent array-CGH genetic testing, both showing a partial...
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Format: | Article |
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2017-07-01
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Series: | Genome Medicine |
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Online Access: | http://link.springer.com/article/10.1186/s13073-017-0452-y |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Claudio Reggiani Sandra Coppens Tayeb Sekhara Ivan Dimov Bruno Pichon Nicolas Lufin Marie-Claude Addor Elga Fabia Belligni Maria Cristina Digilio Flavio Faletra Giovanni Battista Ferrero Marion Gerard Bertrand Isidor Shelagh Joss Florence Niel-Bütschi Maria Dolores Perrone Florence Petit Alessandra Renieri Serge Romana Alexandra Topa Joris Robert Vermeesch Tom Lenaerts Georges Casimir Marc Abramowicz Gianluca Bontempi Catheline Vilain Nicolas Deconinck Guillaume Smits |
spellingShingle |
Claudio Reggiani Sandra Coppens Tayeb Sekhara Ivan Dimov Bruno Pichon Nicolas Lufin Marie-Claude Addor Elga Fabia Belligni Maria Cristina Digilio Flavio Faletra Giovanni Battista Ferrero Marion Gerard Bertrand Isidor Shelagh Joss Florence Niel-Bütschi Maria Dolores Perrone Florence Petit Alessandra Renieri Serge Romana Alexandra Topa Joris Robert Vermeesch Tom Lenaerts Georges Casimir Marc Abramowicz Gianluca Bontempi Catheline Vilain Nicolas Deconinck Guillaume Smits Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability Genome Medicine Functional genomics Promoters Neurodevelopmental disorders Intellectual disability DLG2 |
author_facet |
Claudio Reggiani Sandra Coppens Tayeb Sekhara Ivan Dimov Bruno Pichon Nicolas Lufin Marie-Claude Addor Elga Fabia Belligni Maria Cristina Digilio Flavio Faletra Giovanni Battista Ferrero Marion Gerard Bertrand Isidor Shelagh Joss Florence Niel-Bütschi Maria Dolores Perrone Florence Petit Alessandra Renieri Serge Romana Alexandra Topa Joris Robert Vermeesch Tom Lenaerts Georges Casimir Marc Abramowicz Gianluca Bontempi Catheline Vilain Nicolas Deconinck Guillaume Smits |
author_sort |
Claudio Reggiani |
title |
Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability |
title_short |
Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability |
title_full |
Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability |
title_fullStr |
Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability |
title_full_unstemmed |
Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability |
title_sort |
novel promoters and coding first exons in dlg2 linked to developmental disorders and intellectual disability |
publisher |
BMC |
series |
Genome Medicine |
issn |
1756-994X |
publishDate |
2017-07-01 |
description |
Abstract Background Tissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders. Methods Two pediatric patients with global developmental delay and intellectual disability phenotype underwent array-CGH genetic testing, both showing a partial deletion of the DLG2 gene. From independent human and murine omics datasets, we combined copy number variations, histone modifications, developmental tissue-specific regulation, and protein data to explore the molecular mechanism at play. Results Integrating genomics, transcriptomics, and epigenomics data, we describe two novel DLG2 promoters and coding first exons expressed in human fetal brain. Their murine conservation and protein-level evidence allowed us to produce new DLG2 gene models for human and mouse. These new genic elements are deleted in 90% of 29 patients (public and in-house) showing partial deletion of the DLG2 gene. The patients’ clinical characteristics expand the neurodevelopmental phenotypic spectrum linked to DLG2 gene disruption to cognitive and behavioral categories. Conclusions While protein-coding genes are regarded as well known, our work shows that integration of multiple omics datasets can unveil novel coding elements. From a clinical perspective, our work demonstrates that two new DLG2 promoters and exons are crucial for the neurodevelopmental phenotypes associated with this gene. In addition, our work brings evidence for the lack of cross-annotation in human versus mouse reference genomes and nucleotide versus protein databases. |
topic |
Functional genomics Promoters Neurodevelopmental disorders Intellectual disability DLG2 |
url |
http://link.springer.com/article/10.1186/s13073-017-0452-y |
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doaj-1e373d346a364c37be5ee81901ae95242020-11-24T21:24:57ZengBMCGenome Medicine1756-994X2017-07-019112010.1186/s13073-017-0452-yNovel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disabilityClaudio Reggiani0Sandra Coppens1Tayeb Sekhara2Ivan Dimov3Bruno Pichon4Nicolas Lufin5Marie-Claude Addor6Elga Fabia Belligni7Maria Cristina Digilio8Flavio Faletra9Giovanni Battista Ferrero10Marion Gerard11Bertrand Isidor12Shelagh Joss13Florence Niel-Bütschi14Maria Dolores Perrone15Florence Petit16Alessandra Renieri17Serge Romana18Alexandra Topa19Joris Robert Vermeesch20Tom Lenaerts21Georges Casimir22Marc Abramowicz23Gianluca Bontempi24Catheline Vilain25Nicolas Deconinck26Guillaume Smits27Interuniversity Institute of Bioinformatics in Brussels ULB-VUBDepartment of Neurology, Hôpital Erasme, Université Libre de BruxellesNeuropediatrics, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de BruxellesFaculté de Médecine, Université Libre de BruxellesULB Center of Medical Genetics, Hôpital Erasme, Université Libre de BruxellesInteruniversity Institute of Bioinformatics in Brussels ULB-VUBService de Médecine Génétique, Centre Hospitalier Universitaire Vaudois CHUVDepartment of Public Health and Pediatrics, University of TorinoMedical Genetics, Bambino Gesù Pediatric HospitalS.C. Medical Genetics, Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”Department of Public Health and Pediatrics, University of TorinoLaboratory of Medical Genetics, CHU de Caen - Hôpital ClémenceauService de Génétique MédicaleWest of Scotland Clinical Genetics Service, South Glasgow University HospitalsService de Médecine Génétique, Centre Hospitalier Universitaire Vaudois CHUVS.C. Medical Genetics, Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”Service de Génétique, CHRU de Lille - Hôpital Jeanne de FlandreMedical Genetics, University of SienaService d’Histologie Embryologie Cytogénétique, Hôpital Necker Enfants MaladesDepartment of Clinical Pathology and Genetics, Sahlgrenska University HospitalDepartment of Human Genetics, University of LeuvenInteruniversity Institute of Bioinformatics in Brussels ULB-VUBPediatrics, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de BruxellesInteruniversity Institute of Bioinformatics in Brussels ULB-VUBInteruniversity Institute of Bioinformatics in Brussels ULB-VUBInteruniversity Institute of Bioinformatics in Brussels ULB-VUBNeuropediatrics, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de BruxellesInteruniversity Institute of Bioinformatics in Brussels ULB-VUBAbstract Background Tissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders. Methods Two pediatric patients with global developmental delay and intellectual disability phenotype underwent array-CGH genetic testing, both showing a partial deletion of the DLG2 gene. From independent human and murine omics datasets, we combined copy number variations, histone modifications, developmental tissue-specific regulation, and protein data to explore the molecular mechanism at play. Results Integrating genomics, transcriptomics, and epigenomics data, we describe two novel DLG2 promoters and coding first exons expressed in human fetal brain. Their murine conservation and protein-level evidence allowed us to produce new DLG2 gene models for human and mouse. These new genic elements are deleted in 90% of 29 patients (public and in-house) showing partial deletion of the DLG2 gene. The patients’ clinical characteristics expand the neurodevelopmental phenotypic spectrum linked to DLG2 gene disruption to cognitive and behavioral categories. Conclusions While protein-coding genes are regarded as well known, our work shows that integration of multiple omics datasets can unveil novel coding elements. From a clinical perspective, our work demonstrates that two new DLG2 promoters and exons are crucial for the neurodevelopmental phenotypes associated with this gene. In addition, our work brings evidence for the lack of cross-annotation in human versus mouse reference genomes and nucleotide versus protein databases.http://link.springer.com/article/10.1186/s13073-017-0452-yFunctional genomicsPromotersNeurodevelopmental disordersIntellectual disabilityDLG2 |