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)