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.

Brain dynamics in ASD during movie‐watching show idiosyncratic functional integration and segregation

“…ASD affect 1 of 45 children according to the most recent estimates (Zablotsky, Black, Maenner, Schieve, & Blumberg, 2015), and remain mechanistically poorly understood. However, because a notable fraction of candidate genes relate to synaptic transmission (Persico & Napolioni, 2013; Krumm, O'Roak, Shendure, & Eichler, 2014), ASD are typically perceived as a system‐level condition, which gave rise to many functional magnetic resonance imaging (fMRI) studies attempting to decipher how the autistic brain works.…”

Insights into the Genetic Foundations of Human Communication

“…Other modes of inheritance consistent with sporadic disorder are autosomal recessive, X-linked, and imprinting, and examples of all of these are also found for severe ID (des Portes 2013; Musante and Ropers 2014;Buiting 2010). Recently, sequencing of probands and parents has confirmed that single de novo protein-altering mutations are also causal in a significant proportion of cases (Gilissen et al 2014;Krumm et al 2014;Veltman and Brunner 2012). ID sometimes occurs in the context of a syndromic disorder, in which there are co-occurring developmental defects in other organs (van Bokhoven 2011).…”

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism

“…Gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice in affected versus unaffected children and have far more impacts on the individual [19]. These studies suggest that protein-truncating de novo SNVs contribute to the risk of ASD for about 10%-15% of probands [20]. The burden of de novo mutations affecting genes expressed in the brain is higher in individuals with ASD as compared with controls [3].…”

“…Third, due to exome capture limitations or errors in the reference genome, the coverage of genomic regions is incomplete. Fourth, mutation calls are made from only coding regions, and therefore, noncoding regions are missed that might affect RNA expression or processing [19][20][21].…”