Journal Article

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

Lufin, Nicolas, Dimov, Ivan, Deconinck, Nicolas, Addor, Marie-Claude, Topa, Alexandra, Abramowicz, Marc, Gerard, Marion, Smits, Guillaume, Isidor, Bertrand, Romana, Serge, Casimir, Georges, Reggiani, Claudio, Pichon, Bruno, Petit, Florence, Renieri, Alessandra, Bontempi, Gianluca, Lenaerts, Tom, Joss, Shelagh, Niel-Bütschi, Florence, Sekhara, Tayeb, Digilio, Maria Cristina, Perrone, Maria Dolores, Vermeesch, Joris Robert, Vilain, Catheline, Ferrero, Giovanni Battista, Faletra, Flavio, Coppens, Sandra, Belligni, Elga Fabia

2017

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Animal models / Animals / Autism / Biochemistry, Molecular Biology / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Child / Cognitive ability / Conserved sequence / Copy number / Developmental Disabilities - genetics / Developmental Disabilities - metabolism / DLG2 / Epilepsy / Exons / Female / Fetuses / Functional genomics / Gene deletion / Gene disruption / Gene expression / Genetic screening / Genetics / Genomes / Genomics / Guanylate Kinases - genetics / Human Genetics / Humans / Integration / Intellectual disabilities / Intellectual disability / Intellectual Disability - genetics / Intellectual Disability - metabolism / Life Sciences / Male / Medicine/Public Health / Membrane Proteins - genetics / Metabolomics / Mice / Neural coding / Neurodevelopmental disorders / Patients / Promoter Regions, Genetic / Promoters / Proteins / Schizophrenia / Software / Systems Biology / Tumor Suppressor Proteins - genetics