Widespread Genotype-Phenotype Correlations in Intellectual Disability

Abstract

ABSTRACTBackgroundLinking genotype to phenotype is a major aim of genetics research, yet many complex conditions continue to hide their underlying biochemical mechanisms. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID.MethodsTwo hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical symptoms of complex versus simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered using via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment modules within the full ID network.ResultsPhenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to module.ConclusionsThese data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap.