Genetics of Autism Spectrum Disorder: Current Status and Possible Clinical Applications

Abstract

Autism spectrum disorder (ASD) is one of the most complex behavioral disorders with a strong genetic influence. The objectives of this article are to review the current status of genetic research in ASD, and to provide information regarding the potential candidate genes, mutations, and genetic loci possibly related to pathogenesis in ASD. Investigations on monogenic causes of ASD, candidate genes among common variants, rare de novo mutations, and copy number variations are reviewed. The current possible clinical applications of the genetic knowledge and their future possibilities are highlighted.

Keywords: Autism spectrum disorder; Genetic diagnosis; Syndromic autism; de novo mutations.

Fig. 1. Molecular pathways implicated in neurodevelopmental disorders. RTKs, receptor tyrosine kinases; iGluRs, metabotropic glutamate receptors; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; SREBP, sterol regulatory element-binding proteins; HIF1α, hypoxia-inducible factor 1 alpha; ULK1, unc-51-like kinase 1; ARC, activity-regulated cytoskeleton-associated protein; UBE3A, ubiquitin protein ligase E3A; MeCP2, methyl CpG binding protein 2; FMRP, fragile X mental retardation protein; PI3K/mTOR , phosphatidylinositol 3-kinase/mammalian target of rapamycin; PSD-95, postsynaptic density protein 95; CNTNAP2, Contactin-associated protein-like 2; NF1, neurofibromin 1; PLCβ, Abstract Phospholipase C β; SYNGAP1, Synaptic Ras GTPase-activating protein 1; ERK1/2, extracellular signal-regulated kinase; PTEN, Phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase; PDK1, Pyruvate dehydrogenase lipoamide kinase isozyme 1; PKC, Paroxysmal kinesogenic choreoathetosis, neurological disorder Protein kinase C; AKT, Protein kinase B; AMPK, AMP-activated protein kinase; TSC2, Tuberous Sclerosis Complex 2; TSC1, tuberous sclerosis 1; RHEB, GTP-binding protein Rheb; DEPDC5, DEP domain-containing 5; mTORC1, mammalian target of rapamycin complex 1; mGluR, metabotropic glutamate receptor; SHANK, Shank protein; ATG13, Autophagy-related protein 13; HDAC, Histone deacetylases; CHD8, Chromodomain-helicase-DNA-binding protein 8; MEF2, myocyte enhancer factor-2; RAS, Ras protein; TBC1D7, TBC1 domain family, Member 7; 4E-BPs, eIF4E-binding proteins; FIP200, a ULK-interacting protein; S6K1/2, Anti-RIBOSOMAL S6 KINASE 1/2; HOMER, homer scaffolding protein; RAGA/B, Ras-related GTP binding A/B ortholog; RAGC/D, Ras-related GTP binding C/D ortholog. From M. Sahin and M. Sur, Genes, circuits, and precision therapies for autism and related neurodevelopmental disorders, Science 350, aab3897 (2015). DOI: 10.1126/science.aab3897. Reprinted with permission from The American Association for the Advancement of Science (AAAS).