Lost in Translation: Traversing the Complex Path from Genomics to Therapeutics in Autism Spectrum Disorder

Abstract

Recent progress in the genomics of non-syndromic autism spectrum disorder (nsASD) highlights rare, largeeffect, germline, heterozygous de novo coding mutations. This distinguishes nsASD from later-onset psychiatric disorders where gene discovery efforts have predominantly yielded common alleles of small effect. These differences point to distinctive opportunities for clarifying the neurobiology of nsASD and developing novel treatments. We argue that the path ahead also presents key challenges, including distinguishing human pathophysiology from the potentially pleiotropic neurobiology mediated by established risk genes. We present our view of some of the conceptual limitations of traditional studies of model organisms, suggest a strategy focused on investigating the convergence of multiple nsASD genes, and propose that the detailed characterization of the molecular and cellular landscapes of developing human brain is essential to illuminate disease mechanisms. Finally, we address how recent advances are leading to novel strategies for therapeutics that target various points along the path from genes to behavior.

Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex

“…In contrast, these metrics are comparatively stable over several decades of adulthood (Colantuoni et al, 2011;Jaffe et al, 2018;Kang et al, 2011;Li et al, 2018;Pletikos et al, 2014). Disruptions of these developmentally dynamic regulatory processes are likely to be important contributors to multiple neurodevelopmental and neuropsychiatric disorders (Birnbaum and Weinberger, 2017;Breen et al, 2016;Geschwind and Flint, 2015;McCarroll and Hyman, 2013;Rosti et al, 2014;Sestan and State, 2018;Turner and Eichler, 2018). In keeping with this expectation, analyses of spatiotemporal expression patterns have implicated mid-fetal brain development as a vulnerable process, and the prefrontal cortex as a vulnerable region, for both autism spectrum disorder (ASD) and schizophrenia (SCZ) risk genes (Chang et al, 2015b;Gulsuner et al, 2013;Li et al, 2018; Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, 2015; Parikshak et al, 2013;Satterstrom et al, 2018;Willsey et al, 2013;Xu et al, 2014).…”

Multi-hit autism genomic architecture evidenced from consanguineous families with involvement of FEZF2 and mutations in high-risk genes

“…For the FEZF2 allele-unlinked families, the DAPPLE network is also significant for both direct and indirect nodes (Direct Edges Count P = 3.49 x 10 -2 ; Seed Indirect Degrees Mean P = 1.99 x 10 -2 ; CI Degrees Mean P=1.99 x 10 -3 ). Interestingly, mutations found in de novo CNVs of FEZF2 allele-unlinked families underline the importance of synaptic networks as already reported (5,6,(33)(34)(35). In contrast, results from transmitted and de novo CNVs of FEZF2 allelelinked and unlinked families point to distinct gene classes with adhesion proteins involved in hemophilic interactions, such as clustered protocadherins (36,37), that are known to be involved in the establishment of the diversity of neural circuit assemblies and olfaction pathways.…”

“…Our aim was to test the hypothesis that a single damaging mutation in a limited set of high-risk genes, asproposed in previous studies (5,6,35), can be sufficient to cause ASD. Our data reveal a clear multi-hit organisation involving a homozygous FEZF2 allele, a damaging FEFZ2 mutation, mutations in ASD high-risk genes, and other gene variants.…”

“…In contrast, transmitted SNVs for FEZF2 allele-unlinked families (N=931) display enrichment in genes of GO biological process GO:0007155 cell adhesion (P=1.52E -06 ). Studies leveraging the statistical power afforded by rare de novo putatively damaging variants have identified more than 65 genes strongly associated with ASD (5,35). The most deleterious variants in the highest confidence subset of these genes (n = 30) as a group confer ~20-fold increase in risk (5).…”

Functional connectivity differences in early infancy precede autism symptoms: a multivariate pattern analysis

“…For instance, ASD-associated risk genes are shown to converge upon co-expression networks in the frontal cortex during fetal brain development [24]. By disrupting key neurobiological processes (such as neuronal migration, synaptogenesis, and myelination) in the frontal cortex, genes associated with ASD risk may particularly impact frontal functional connectivity [63]. Further evidence linking these genes to specific frontal disruptions comes from copy number variations and single gene disorders that confer susceptibility for ASD and are also associated with decreased frontotemporal and fronto-parietal connectivity [64].…”