Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability

Genome Medicine, Jul 2017

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.

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Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability

Reggiani et al. Genome Medicine Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability Claudio Reggiani 0 1 14 20 Sandra Coppens 1 14 19 25 Tayeb Sekhara 1 14 17 25 Ivan Dimov 1 14 24 Bruno Pichon 1 2 14 23 Nicolas Lufin 0 1 2 14 23 Marie-Claude Addor 1 14 22 Elga Fabia Belligni 1 14 27 Maria Cristina Digilio 1 14 26 Flavio Faletra 1 14 21 Giovanni Battista Ferrero 1 14 27 Marion Gerard 1 10 14 Bertrand Isidor 1 11 14 Shelagh Joss 1 8 14 Florence Niel-Bütschi 1 14 22 Maria Dolores Perrone 1 14 18 21 Florence Petit 1 9 14 Alessandra Renieri 1 6 7 14 Serge Romana 1 4 5 14 Alexandra Topa 1 3 14 Joris Robert Vermeesch 1 13 14 Tom Lenaerts 0 1 12 14 20 Georges Casimir 1 14 15 Marc Abramowicz 0 1 2 14 23 Gianluca Bontempi 0 1 14 20 Catheline Vilain 0 1 2 14 16 23 Nicolas Deconinck 1 14 25 Guillaume Smits 0 1 2 14 16 23 0 Interuniversity Institute of Bioinformatics in Brussels ULB-VUB , Brussels 1050 , Belgium 1 work Gianluca Bontempi , Catheline Vilain, Nicolas Deconinck, and Guillaume Smits 2 ULB Center of Medical Genetics, Hôpital Erasme, Université Libre de Bruxelles , Brussels 1070 , Belgium 3 Department of Clinical Pathology and Genetics, Sahlgrenska University Hospital , Gothenburg 413 45 , Sweden 4 Service d'Histologie Embryologie Cytogénétique, Hôpital Necker Enfants Malades , Paris 75015 , France 5 Université Paris Descartes - Institut IMAGINE , Paris 75015 , France 6 Medical Genetics, University of Siena , Siena 53100 , Italy 7 Genetica Medica, Azienda Ospedaliera Universitaria Senese , Siena 53100 , Italy 8 West of Scotland Clinical Genetics Service, South Glasgow University Hospitals , Glasgow G51 4TF , UK 9 Service de Génétique, CHRU de Lille - Hôpital Jeanne de Flandre , Lille 59000 , France 10 Laboratory of Medical Genetics, CHU de Caen - Hôpital Clémenceau , Caen, 14033 Caen Cedex , France 11 Service de Génétique Médicale , CHU de Nantes, Nantes, 44093 Nantes Cedex 1 , France 12 AI lab, Vrije Universiteit Brussel , Brussels 1050 , Belgium 13 Department of Human Genetics, University of Leuven , Leuven 3000 , Belgium 14 Authors' contributions Conception and design: CR, GB, CV, ND, GS. Analysis: CR, CV, ND, GS. Interpretation of data: CR, GB, CV, ND, GS. Acquisition of data: CR, SC, TS, ID, BP, NL, CV, ND, GS. Wrote the paper: CR, SC, CV, ND, GS. Contributed samples/ materials/tools/resources: CR, SC, TS, BP, MCA, EFB, MCD, FF, GBF, MG, BI, SJ, FNB, MDP, FP, AR, SR, AT, JRV, TL, GC, MA, GB, CV, ND, GS. The three second Critical revision: CR, ID, MA, GB, CV, ND, GS. Final approval: all authors 15 Pediatrics, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles , Brussels 1020 , Belgium 16 Genetics, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles , Brussels 1020 , Belgium 17 Present address: Neuropediatrics, Clinique Saint-Anne Saint-Rémy - CHIREC , Brussels 1070 , Belgium 18 Present address: Assisted Fertilization Department, Casa di Cura Città di Udine , Udine 33100 , Italy 19 Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles , Brussels 1070 , Belgium 20 Machine Learning Group, Université Libre de Bruxelles , Brussels 1050 , Belgium 21 S.C. Medical Genetics, Institute for Maternal and Child Health - IRCCS “Burlo Garofolo” , Trieste 34137 , Italy 22 Service de Médecine Génétique, Centre Hospitalier Universitaire Vaudois CHUV , Lausanne 1011 , Switzerland 23 ULB Center of Medical Genetics, Hôpital Erasme, Université Libre de Bruxelles , Brussels 1070 , Belgium 24 Faculté de Médecine, Université Libre de Bruxelles , Brussels 1070 , Belgium 25 Neuropediatrics, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles , Brussels 1020 , Belgium 26 Medical Genetics, Bambino Gesù Pediatric Hospital , Rome 00165 , Italy 27 Department of Public Health and Pediatrics, University of Torino , Turin 10126 , Italy 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 (...truncated)


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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, 2017, pp. 67, Volume 9, Issue 1, DOI: 10.1186/s13073-017-0452-y