Arion Yu

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is classified by deficiencies in social communication and repetitive behaviors.¹ The cost of treating ASD patients, including through educational resources, health services, and ancillary parental support was $268 billion in 2015, and estimated to climb to $461 billion by 2025.³ With all the costs associated with treating ASD, efforts have been made to further understand the complex etiology of ASD. It is believed that ASD results from a complex combination of genetic and environmental factors.³

Objective: In this narrative review, we explored a potential link between a deficiency in Chromodomain Helicase DNA Binding Protein 8 (CHD8) and the development of ASD-like characteristics.¹

Search Methods: An online search in the PubMed database was conducted from 2017 to 2022 using the following keywords: “autism”, “CHD8”, “neurodevelopment”.

Results: A study conducted in 2007 first demonstrated the role of CHD8 in the development of ASD when a loss-of-function mutation in two unrelated children resulted in cognitive development and developmental delays.¹ Further studies have sequenced the CHD8 gene and identified consistent phenotypical and behavioral characteristics among individuals with the CHD8 mutation such as macrocephaly, cognitive impairment, and social deficits. Studies have attempted to replicate these findings in mice through measurement of brain size for macrocephaly, and behavioral assays to observe social behavior. Brain MRIs found an increase in intraocular distance and brain volume in CHD8-deficient mice compared to wild-type mice.⁴ RNA sequencing also revealed widespread upregulation and downregulation of genes in various brain regions of the developing mouse brain.⁴ Additionally, CHD8-deficient mice spent less time in the center during Open Field Tests compared to wild-type littermates.⁴ Additional studies confirmed the macrocephaly phenotype through brain MRIs to measure cortical anterior-posterior length of CHD8-deficient mice and found a 7% increase in maximum cortical length.⁵ CHD8-deficient mice also demonstrated less novel object recognition in behavioral assays.⁵ Utilizing 5-ethynl-2-deoxyuridine (EdU) assays, it was found that CHD8-deficient mice had significantly elevated neuron proliferation markers, roughly a 15.9% increase in EdU+ cells in germinal cortical ventricular and subventricular zones of mutant mice.⁵ Using Tau and MAP2 markers, it was found that loss of CHD8 inhibited axon and dendrite growth.⁶ In utero electroporation measured the degree of Enhanced Green Fluorescent protein (EGFP) positive cell migration and found that CHD8-deficient mice demonstrated a delay in neuron migration at embryonic age 18.5.⁶ In order to demonstrate the longitudinal effects of CHD8 mutations beyond embryonic age, mutant mice were subject to behavioral assays at 6 months and 1 year of age.7 CHD8-deficient mice spent less time in the center during open field tests, and that time increased at 1 year of age.⁷ RNA sequencing showed delays in gene clusters associated with neuronal maturation and communication, and at 12 months, the gene cluster associated with the unfolded protein response was reduced in CHD8-deficient mice.⁷ Replicating these studies in cerebral organoids produced similar results.⁸

Conclusions: Patients with CHD8 mutations display macrocephaly, abnormal social communication, and impaired neurodevelopment similar to those seen in patients with ASD. Attempts to replicate these observations in CHD8-deficient mice has produced consistent results. The role of CHD8 in neurodevelopment could be due to a combination of downregulating and upregulating transcriptional activity in brain regions. CHD8 mutations cause increased neuron proliferation, but delayed axon migration, which could explain the macrocephaly and social behavior. Further studies could investigate potential therapies through the reintroduction of the CHD8 gene.

Works Cited:

1. Jiang CC, Lin LS, Long S, et al. Signalling pathways in autism spectrum disorder: mechanisms and therapeutic implications. Signal Transduct Target Ther. 2022;7(1):229. Published 2022 Jul 11. doi:10.1038/s41392-022-01081-0
2. Sharma SR, Gonda X, Tarazi FI. Autism Spectrum Disorder: Classification, diagnosis and therapy. Pharmacol Ther. 2018;190:91-104. doi:10.1016/j.pharmthera.2018.05.007
3. Weissberg O, Elliott E. The Mechanisms of CHD8 in Neurodevelopment and Autism Spectrum Disorders. Genes (Basel). 2021;12(8):1133. Published 2021 Jul 26. doi:10.3390/genes12081133
4. Platt RJ, Zhou Y, Slaymaker IM, et al. Chd8 Mutation Leads to Autistic-like Behaviors and Impaired Striatal Circuits. Cell Rep. 2017;19(2):335-350. doi:10.1016/j.celrep.2017.03.052
5. Gompers AL, Su-Feher L, Ellegood J, et al. Germline Chd8 haploinsufficiency alters brain development in mouse. Nat Neurosci. 2017;20(8):1062-1073. doi:10.1038/nn.4592
6. Xu Q, Liu YY, Wang X, et al. Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons. Mol Autism. 2018;9:65. Published 2018 Dec 19. doi:10.1186/s13229-018-0244-2
7. Jiménez JA, Ptacek TS, Tuttle AH, et al. Chd8 haploinsufficiency impairs early brain development and protein homeostasis later in life [published correction appears in Mol Autism. 2021 May 8;12(1):33]. Mol Autism. 2020;11(1):74. Published 2020 Oct 5. doi:10.1186/s13229-020-00369-8
8. Villa CE, Cheroni C, Dotter CP, et al. CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories. Cell Rep. 2022;39(1):110615. doi:10.1016/j.celrep.2022.110615