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

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 and
Guillaume SmitsEmail author

Genome Medicine20179:67

https://doi.org/10.1186/s13073-017-0452-y

Received: 16 January 2017

Accepted: 20 June 2017

Published: 19 July 2017

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.