A de novo convergence of autism genetics and molecular neuroscience

Abstract

Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental disorders with large genetic components, but identification of pathogenic genes has proceeded slowly because hundreds of loci are involved. New exome sequencing technology has identified novel rare variants and has found that sporadic cases of ASD/ID are enriched for disruptive de novo mutations. Targeted large-scale resequencing studies have confirmed the significance of specific loci, including chromodomain helicase DNA binding protein 8 (CHD8), sodium channel, voltage-gated, type II, alpha subunit (SCN2A), dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), and catenin (cadherin-associated protein), beta 1, 88 kDa (CTNNB1, beta-catenin). We review recent studies and suggest that they have led to a convergence on three functional pathways: (i) chromatin remodeling; (ii) wnt signaling during development; and (iii) synaptic function. These pathways and genes significantly expand the neurobiological targets for study, and suggest a path for future genetic and functional studies.

Keywords: autism genetics; autism spectrum disorder; copy number variant; exome sequencing; intellectual disability; single nucleotide variant.

Figure 1

Estimating the number of autism spectrum disorder (ASD)/intellectual disability (ID) risk genes. We estimate the number of ASD and ID genes, using an adaptation of the ‘hidden species problem’ based on the ratio of genes with multiple de novo mutations to all genes with de novo mutations. For each estimate, all genes with recurrent de novo mutations are considered pathogenic, as well as a defined fraction of mutations in genes observed just once (because all de novo mutations are unlikely to be pathogenic). Including more of these singleton mutations as pathogenic, as well as including a broader range of mutation type, exponentially increases the number of ASD and ID risk loci. Thus, considering a disease model in which 15% of all truncating de novo mutations are sufficient and pathogenic, only approximately 50 genes are expected to be similarly sufficient in their pathogenicity; however, by including missense mutations, the number of loci rises dramatically [to over 400 loci when 15% of de novo single nucleotide variants (SNVs) are considered pathogenic]. Taken together, this model highlights the locus heterogeneity underlying the genetic etiology of ASD and ID and suggests that the etiology of a large proportion of ASD/ID cases may not be due to a single de novo mutation (truncating or missense); rather, these cases may be the result of a complex set of interactions between multiple mutations, including SNVs, indels, and copy number variants (CNVs). The shaded area indicates the 95% confidence interval (CI) around the estimate.

Figure 2

The location of de novo truncating mutations in the top five autism spectrum disorder (ASD) and intellectual disability (ID) genes. Red markers indicate locations of de novo mutations in ASD and ID cases; green markers indicate locations of truncating mutations in the Exome Sequencing Project (ESP) database of over 6500 samples (see Table 2 for details). Mutation codes: S, stop-gain; Fs, frameshift; Ss, splice-site mutation; ΔAA, amino-acid loss (non-frameshifting). Blocks indicate annotated protein domains from UniProt. Domain names, top to bottom: CD, chromodomain; DEX, helicase ATP-binding; HELC, helicase C-terminal; TM, transmembrane domain; IQ, IQ domain; PDZ, PDZ-binding motif; LOC, bipartite nuclear localization signal; STK, serine/threonine protein kinase; PH, pleckstrin homology domain; C2, C2 domain; SH3, SRC homology 3 domain.

Figure 3

Predicted proteins disrupted by genic de novo mutations in autism spectrum disorder (ASD) and intellectual disability (ID) form a central connected network. Proteins corresponding to genes with de novo truncating mutations (red nodes) or selected missense mutations (blue nodes) in four ASD exome studies and two ID exome studies are connected using experimentally derived protein–protein interaction (PPI) data from StringDB [69]. Only medium- and high-confidence experimental interactions are shown, although we note that these may not always represent local interactions, protein–protein interactions, or interactions within the same subcellular compartment. Peripheral nodes (lighter shades) represent genes with additional truncating de novo mutations, which are separated from the central network by only a single node (white nodes; for this analysis we excluded SUMO1/SUMO2 and UBC, which are highly connected but nonspecific nodes).

Figure 4

Chromodomain helicase DNA binding protein 8 (CHD8) and beta-catenin [catenin (cadherin-associated protein), beta 1, 88 kDa; CTNNB1] form putative regulatory networks for head size. (A) Truncating mutations in CTNNB1 (red arrows) and CHD8 (blue arrows) are found in patients with small and large head circumference, respectively. The gray histogram represents the background distribution of age- and sex-corrected head circumference Z-scores for 2446 probands from the Simons Simplex Collection (SSC) [36]. [The exact head circumference for one case (marked with *) with clinically reported microcephaly could not be determined, so the Z-score was estimated at −2.0, or the clinical threshold for microcephaly.] (B) A putative regulatory model of head growth where CHD8 negatively regulates CTNNB1 [73]; CTNNB1 promotes head growth and constitutive overexpression of CTNNB1 in mice results in macrocephaly [72].