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CHD8 is a leading candidate gene for autism risk and may represent a specific genetic subtype of autism.

What is CHD8?

Located on the long arm of chromosome 14 at position 11.2 CHD8 belongs to the chromodomain-helicase-DNA binding protein family. CHD8 codes for an ATP-dependent chromatin-remodeling factor that binds to β-catenin and negatively regulates Wnt signaling. CHD8 regulates the expression of a network of genes, including other autism risk genes, and may play an important role in fetal brain development.1,2,3 CHD8 is expressed widely throughout the adult brain, but its expression seems to be highest during the early prenatal period of human development.

Relevance to autism:

CHD8 is among hundreds of genes that contribute to autism. The significant genetic heterogeneity of this disorder has, historically, made it difficult to implicate individual genes in autism etiology using traditional approaches to gene discovery, but next-generation sequencing technologies have begun to unravel some of the genetic complexity of autism. The use of whole-exome sequencing with large autism cohorts has allowed for the detection of very small, rare changes to ‘high-confidence’ risk genes for autism. CHD8 has emerged as a leading candidate gene for autism risk in several landmark genetic research studies. Exome sequencing of 209 children with autism from the Simons Simplex Collection (SSC) by O’Roak et al. revealed recurrent loss-of-function mutations (LOF) in only two genes, one of which was CHD8.4 In a concurrent study, Talkowski et al. sequenced balanced chromosomal abnormalities (BCAs) in a group of individuals with neurodevelopmental disorders and found a single disruption to CHD8 in an individual diagnosed with autism.5 Using a modified molecular inversion probe (MIP) strategy, O’Roak et al. targeted 44 candidate genes in 2,446 individuals with autism from SSC and found eight individuals with recurrent truncating mutations in CHD8.6 Overall, 0.35% of SSC participants were found to have a mutation in CHD8. These research studies provided substantial evidence that CHD8 mutations are involved in autism risk.

Twenty-four genes currently meet SFARI Gene criteria for a high-confidence autism risk gene. Research estimates that likely gene-disrupting mutations (LGD), including CHD8, account for about 10 percent of simplex autism cases.

CHD8 phenotype:

To better understand the complicated relationship between autism clinical phenotype and genotype, novel approaches to studying autism genetics have been proposed. One such method is a “genotype-first” approach, in which individuals are identified based on specific gene mutations and recontacted for comprehensive phenotyping in clinic. Applying this method to autism in an effort to determine whether CHD8 represents a specific genetic subtype of autism, Bernier and colleagues resequenced CHD8 in 3,730 children with autism or developmental delay and identified 15 independent truncating mutations. The majority of these mutations (13/15) were de novo, and no disruptive mutations were observed in a large control group of unaffected siblings. Eight subjects were subsequently recontacted and participated in a comprehensive, structured characterization study.

Data from this group were combined with information from clinical reports on seven previous subjects. A clear phenotypic profile emerged from the study of this cohort. Thirteen of the 15 individuals (87 percent) met strict diagnostic criteria for autism. Eighty percent of individuals had macrocephaly, a rate significantly greater than that found in SSC participants without mutations in CHD8. Head circumference velocity data indicated early orbital head growth in the first two months following birth, with sustained large head growth at or above the 97th percentile throughout early childhood. Markedly similar and distinct facial features were also observed, including a prominent forehead, wide-set eyes, broad nose with full nasal tip, and pointed chin. The majority (80 percent) of subjects reported gastrointestinal issues, primarily significant constipation. Sleep problems, particularly problems with falling asleep, were also frequently reported. Cognitive impairment was apparent, but varied widely, with some individuals falling within the normal range. Nine patients presented with co-occurring intellectual disability.

Animal studies also support a common phenotype for disruptive mutations in CHD8. Both zebrafish and mouse models recapitulate aspects of the human phenotype. Mice with mutations to CHD8 present with macrocephaly and craniofacial abnormalities, as well as learning and memory deficits.7,8,9 Some studies have found that these mutant mice demonstrate autism-like behavioral characteristics that include anxiety, repetitive behavior, and mild differences in social behavior. Other mouse studies have not identified the same social impairments, which could reflect differences in study methodology. Morphant zebrafish develop macrocephaly and have problems with GI motility, similar to the issues with constipation found in humans with disruptions in CHD8.

Future work that continues to define genetic subtypes of autism by tying clinical phenotypes to specific genetic etiologies will help to refine the autism spectrum and will allow for the targeting of treatments and therapies.