Strict network analysis of evolutionary conserved and brain-expressed genes reveals new putative candidates implicated in Intellectual Disability and in Global Development Delay.

Objectives: Intellectual Disability (ID) and Global Development Delay (GDD) are frequent reasons for referral to genetic services and although they present overlapping phenotypes concerning cognitive, motor, language, or social skills, they are not exactly synonymous. Aiming to better understand independent or shared mechanisms related to these conditions and to identify new candidate genes, we performed a highly stringent protein-protein interaction network based on genes previously related to ID/GDD in the Human Phenotype Ontology portal.Methods: ID/GDD genes were searched for reliable interactions through STRING and clustering analysis was applied to detect biological complexes through the MCL algorithm. Six coding hub genes (TP53, CDC42, RAC1, GNB1, APP, and EP300) were recognized by the Cytoscape NetworkAnalyzer plugin, interacting with 1,625 proteins not yet associated with ID or GDD. Genes encoding these proteins were explored by gene ontology, associated diseases, evolutionary conservation, and brain expression.Results: 172 new putative genes playing a role in enriched processes/pathways previously related to ID and GDD were revealed, some of which were already postulated to be linked to ID/GDD in additional databases.Conclusions: Our findings expanded the etiological genetic landscape of ID/GDD and showed evidence that both conditions are closely related at the molecular and functional levels.