Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules. Author Summary Intellectual Disability (ID) affects 2% of our population and is associated with many different disorders. Although more than 400 causative genes (‘ID genes’) have been identified, their function remains poorly understood and the degree to which these disorders share a common molecular basis is unknown. Here, we systematically characterized behavioral and morphological phenotypes associated with 270 conserved ID genes, using the Drosophila eye and photoreceptor neurons as a model. These and follow up approaches generated previously undescribed genotype-phenotype associations for the majority (180) of ID gene orthologs, and identified, among others, 16 novel regulators of basal neurotransmission. Importantly, groups of genes that show the same phenotype in Drosophila are highly enriched in known connectivity, also share increased phenotypic similarity in humans and successfully predicted novel gene functions. In total, we mapped 26 conserved functional modules that together comprise 100 ID gene orthologs. Our findings provide unbiased evidence for the long suspected but never experimentally demonstrated functional coherence among ID disorders. The identified conserved functional modules may aid to develop therapeutic strategies that target genetically heterogeneous ID patients with a common treatment.
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