TY - JOUR
T1 - Novel promoters and coding first exons in DLG2 linked to developmental disorders and intellectual disability
AU - Reggiani, Claudio
AU - Coppens, Sandra
AU - Sekhara, Tayeb
AU - Dimov, Ivan
AU - Pichon, Bruno
AU - Lufin, Nicolas
AU - Addor, Marie-Claude
AU - Belligni, Elga Fabia
AU - Digilio, Maria Cristina
AU - Faletra, Flavio
AU - Ferrero, Giovanni Battista
AU - Gerard, Marion
AU - Isidor, Bertrand
AU - Joss, Shelagh
AU - Niel-Butschi, Florence
AU - Perrone, Maria Dolores
AU - Petit, Florence
AU - Renieri, Alessandra
AU - Romana, Serge
AU - Topa, Alexandra
AU - Vermeesch, Joris Robert
AU - Lenaerts, Tom
AU - Casimir, Georges
AU - Abramowicz, Marc
AU - Bontempi, Gianluca
AU - Vilain, Catheline
AU - Deconinck, Nicolas
AU - Smits, Guillaume
PY - 2017/7/19
Y1 - 2017/7/19
N2 - 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.
AB - 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.
KW - Animals
KW - Child
KW - Developmental Disabilities/genetics
KW - Exons
KW - Female
KW - Guanylate Kinases/genetics
KW - Humans
KW - Intellectual Disability/genetics
KW - Male
KW - Membrane Proteins/genetics
KW - Mice
KW - Promoter Regions, Genetic
KW - Tumor Suppressor Proteins/genetics
UR - http://www.scopus.com/inward/record.url?scp=85025079330&partnerID=8YFLogxK
U2 - 10.1186/s13073-017-0452-y
DO - 10.1186/s13073-017-0452-y
M3 - Article
VL - 9
SP - 67
JO - Genome Medicine
JF - Genome Medicine
SN - 1756-994X
IS - 1
M1 - 67
ER -