Widespread Genotype-Phenotype Correlations in Intellectual Disability

Abstract

BackgroundLinking 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.

Meta‐Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort

“…Regarding the two prioritized genes ( PRPF8 and RBM14 ) as possible novel candidates to ASD, PRPF8 is highly expressed in brain and encodes a protein that acts as a scaffold for spliceosome complexes, being the most evolutionarily conserved protein of the spliceosome [Grainger & Beggs, ; Maciejewski & Padgett, ]. PRPF8 is essential to pre‐mRNA splicing and is required in all tissues, being recently described as a main molecular hub linking autism and epilepsy in gene‐interaction networks [Casanova, Gerstner, Sharp, & Casanova, ]. Furthermore, we identified another six ASD individuals harboring de novo variants in PRPF8 , resulting in a nominal significant number compared to the expected rate to this gene [Samocha et al, ].…”

Autism risk genes are evolutionarily ancient and maintain a unique feature landscape that echoes their function

“…In order to address clinically associated confounds, we also compared ASD risk genes to a group of syndromic ID‐associated genes (not linked with autism), which we had compiled and reported in a previous study [Casanova et al, , ]. We found that gene/protein lengths were significantly longer in the ASD genes compared to the ID genes ( P < 0.0001).…”

“…This agrees with our earlier study [Casanova et al, ], which reported a functional enrichment of epigenetic regulators among many of the same genes. These genes are also strongly implicated in autism‐associated genetic syndromes accompanied by widespread dysmorphic features, indicating that they play vital roles not just in corticogenesis but morphogenesis in general [Casanova et al, ].…”

“…The ASD gene set was compiled using a combination of the SFARI database (categories 1–2 and syndromic ratings) and the data described in Casanova, Sharp, Chakraborty, Sumi, and Casanova [], the latter comprising a collection of largely syndromic major effect genes associated with autism ( N = 157 genes) [Abrahams et al, ]. Comparison intellectual disability (ID) genes (unassociated with autism) were borrowed from Casanova et al [, ] ( N = 152). All genes even weakly associated with autism, including single case reports, have been removed providing a “pure” list of ID genes (Supplementary Material 1, tab “ID_genes”).…”

“…That same research group went on to study the effects of topoisomerase inhibition on synaptic genes, many of which overlap autism risk, finding that synaptic protein expression and synaptic transmission were significantly impaired [Mabb et al, ]. Many of the long neuronal genes implicated in ASD are downstream targets of risk genes such as the Rett's‐linked, MECP2 , and Fragile X syndrome‐associated, FMR1 , both of which have recently been identified by our group as major hubs linking sizable gene clusters associated with syndromic autism [Casanova, Gerstner, Sharp, Casanova, & Feltus, ; Gabel et al, ; Ouwenga & Dougherty, ].…”