Relevance to Autism

Recurrent mutations in the CHD8 gene have been identified in multiple individuals with ASD as described below. O'Roak et al., 2012a reported 2 de novo loss-of-function (LoF) mutations in CHD8 among 209 simplex ASD families (PMID 22495309). In a screen of 44 genes in 2,446 ASD probands from the Simons Simplex Collection, O'Roak et al., 2012b identified 6 additional de novo CHD8 LoF mutations (PMID 23160995). A ninth de novo LoF variant in CHD8 in an ASD proband from the Simons Simplex Collection was observed in Iossifov et al., 2014 (PMID 25363768). Talkowski et al., 2012 (PMID 22521361) showed that CHD8 is among 33 loci with balanced chromosomal abnormalities in individuals with ASD or other neurodevelopmental disorders. Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified CHD8 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Additional LoF variants in CHD8 were identified in children with developmental delay and ASD in Bernier et al., 2014 (PMID 24998929); a phenotypic comparison of patients with CHD8 variants in this report identified recurrent phenotypes and dysmorphic facial features suggestive of a syndromic form of ASD. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified CHD8 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a DNA helicase that functions as a transcription repressor by remodeling chromatin structure. It binds beta-catenin and negatively regulates Wnt signaling pathway, which plays a pivotal role in vertebrate early development and morphogenesis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

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References

Model Summary

Chd8 null mice die in embryonic stages (E8.5-E12.5). Heterozygous Chd8 mutant mice display ASD-like behaviors such as increased anxiety, impaired social interaction and social memory, and increased perseveration. Chd8 hets also have decreased length of intestine, slower intestinal transit, and impaired sensory. Chd8 knockdown brains exhibit abnormal corticogenesis and also display increased anxiety and decreased social approach. The Wnt-beta-catenin signaling pathway is down-regulated in Chd8 knockdowns and the Chd8 related phenotypes can be rescued by expressing beta-catenin.

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