Abstract
BackgroundTissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders.MethodsTwo 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.ResultsIntegrating 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.ConclusionsWhile 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.
Highlights
Tissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders
Identification of novel DLG2 genomic elements (HPs) In the Université Libre de Bruxelles (ULB) cohort, DECIPHER, and the literature we found 29 patients with a monogenic deletion involving the DLG2 gene (Table 1; see “Methods”)
In our effort to explain why intragenic DLG2 deletions occur exclusively in the 79 region, we noticed that 10/29 (34%) patients have only intronic aberrations, three of which have that intronic deletion as a single variation reported in DECIPHER (DECIPHER 292620, 300109, 300111; Fig. 1), possibly suggesting pathogenic involvement of yet unknown functional elements in intron 7 or 8 of DLG2
Summary
Tissue-specific integrative omics has the potential to reveal new genic elements important for developmental disorders. Neurodevelopmental disorders (NDDs) are impairments of the growth, development, and function of the brain They show vast genetic heterogeneity, pleiotropy, monogenic to polygenic origin, and age-related phenotypic variability [1,2,3,4,5,6]. The formal diagnosis of ID requires cognitive testing, which is inaccurate below 5 years of age In this age category, the term global developmental delay (GDD) is considered more appropriate [8]. The development of higher resolution genetic screening methods has underlined the prevalence of genetic anomalies, such as copy number variations (CNVs), in children with ID [9] Many of these CNVs occur de novo, but some can be inherited from an asymptomatic parent and be clinically significant, increasing the difficulty for genetic counseling [10, 11]. One could be the presence of yet uncharacterized functional genomic regions
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