Widespread Genotype-Phenotype Correlations in Intellectual Disability

Abstract

Background: Linking genotype to phenotype is a major aim of genetics research, yet the underlying biochemical mechanisms of many complex conditions continue to remain elusive. 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.Methods: Two hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical manifestations of complex vs. 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 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 patterns within subgroups.Results: Phenotypic 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 gene set.Conclusions: These 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, 2005;Maciejewski & Padgett, 2012]. 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, 2018]. 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 .…”

The Relationship between Autism and Ehlers-Danlos Syndromes/Hypermobility Spectrum Disorders

“…Meanwhile, a substantial minority on the autism spectrum display rare genetic variants that appear to be the primary cause of their conditions [ 5 ]. Often the autistic phenotype associated with these rare variants is secondary to a genetic syndrome (aka, syndromic autism) and is accompanied by intellectual disability and other physical impairments such as multiple congenital anomalies [ 6 ]. Popular examples of syndromic autism include fragile X syndrome (FXS) (1–5:10,000) and tuberous sclerosis (TSC) (1–5:10,000), but also include even less well known and even rarer syndromes such as Lowe syndrome (OCRL) (1:500,000) and mucopolysaccharidosis type 3 (MPS3) (1–9:1,000,000) [ 7 , 8 ].…”

“…Popular examples of syndromic autism include fragile X syndrome (FXS) (1–5:10,000) and tuberous sclerosis (TSC) (1–5:10,000), but also include even less well known and even rarer syndromes such as Lowe syndrome (OCRL) (1:500,000) and mucopolysaccharidosis type 3 (MPS3) (1–9:1,000,000) [ 7 , 8 ]. To date, there are more than 60 monogenic syndromes with high penetrance for autism, as well as other forms of syndromic autism that are the result of larger chromosomal abnormalities [ 6 , 9 , 10 ]. The severity of the autism phenotype varies across the entire spectrum, although individuals with rare (often de novo) deleterious gene variants tend to be more severely affected; meanwhile, individuals of average or above-average cognitive ability tend to harbor a higher polygenic load of small effect variants, which are often inherited and may also be linked with the broader autism phenotype (BAP) in parents and siblings (reviewed in [ 11 , 12 ]).…”

The Developmental Gene Hypothesis for Punctuated Equilibrium: Combined Roles of Developmental Regulatory Genes and Transposable Elements

“…They are typically expressed across multiple tissue types, potentially leading to shared changes across many organ systems when germline mutations do occur . This can be seen, for example, in many human‐specific mutation events in DevReg genes that often lead not only to intellectual disability but multiple congenital anomalies . In addition, many genes associated with rare human genetic diseases share similar structural, functional, and conservation profiles as those reported by Casanova et al., reinforcing the concept of their importance in development and human health .…”