title: 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.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Niklas
authors.initials: N
authors.lastname: Krumm
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: O'Roak
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA; Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA, USA. Electronic address: eee@gs.washington.edu.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D059472:Exome / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D009488:Neurosciences / Q000639:trends
keywords: autism genetics; autism spectrum disorder; copy number variant; exome sequencing; intellectual disability; single nucleotide variant