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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.    Electronic supplementary material  The online version of this article (doi:10.1186/s13073-017-0452-y) contains supplementary material, which is available to authorized users.

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