Elsevier

Biological Psychiatry

Volume 87, Issue 2, 15 January 2020, Pages 123-131
Biological Psychiatry

Archival Report
Clinical Phenotypes of Carriers of Mutations in CHD8 or Its Conserved Target Genes

https://doi.org/10.1016/j.biopsych.2019.07.020Get rights and content

Abstract

Background

Variants disruptive to CHD8 (which codes for the protein CHD8 [chromodomain-helicase-DNA-binding protein 8]) are among the most common mutations revealed by exome sequencing in autism spectrum disorder (ASD). Recent work has indicated that CHD8 plays a role in the regulation of other ASD-risk genes. However, it is unclear whether a possible shared genetic ontology extends to the phenotype.

Methods

This study (N = 143; 42.7% female participants) investigated clinical and behavioral features of individuals ascertained for the presence of a known disruptive ASD-risk mutation that is 1) CHD8 (CHD8 group) (n = 15), 2) a gene targeted by CHD8 (target group) (n = 22), or 3) a gene without confirmed evidence of being targeted by CHD8 (other gene group) (n = 106).

Results

Results indicated shared features between the CHD8 and target groups that included less severe adaptive deficits in communication skills, similar functional language, more social motivation challenges in those with ASD, larger head circumference, higher weight, and lower seizure prevalence relative to the other gene group.

Conclusions

These similarities suggest broader genetic ontology accounts for aspects of phenotypic heterogeneity. Improved understanding of the relationships between related disruptive gene events may lead us to improved understanding of shared mechanisms and lead to more focused treatments for individuals with known genetic mutations.

Section snippets

Participants

Participants included 143 individuals (range, 44 months of age to 28.3 years of age; 42.7% female, 126 white) with disruptive mutations to ASD-associated risk genes. Consistent with a genetics-first approach, recruitment was not contingent on specific clinical diagnoses (e.g., ASD or no ASD). Participants were ascertained following identification of a disruptive genetic variant through clinical genetic testing (n = 80) or genetic testing conducted during participation in a research study in

Autism Symptoms

Consistent with the CHD8 phenotype (11), all children with CHD8 mutations in this cohort were diagnosed with ASD. Importantly, the prevalence rate of ASD was higher in the CHD8 group relative to both the target group (70.6%) (χ21 = 5.23, p = .022) and the other gene group (78%) (χ21 = 4.26, p = .039). No differences were found between prevalence of ASD between the target and other gene groups (p = .56). Group differences in ADOS-2 CSS (Figure 1) indicated increased severity of ASD symptoms in

Discussion

In this study, we characterized phenotypic profiles of groups of individuals with genetic mutations associated with ASD to evaluate a possible converging biological pathway associated with disruptive mutations to CHD8 and genes directly regulated by CHD8. Overall, phenotypic comparisons supported our hypothesis that the CHD8 and target groups were more similar to each other than to the other gene group. Specifically, we found that the CHD8 and target groups were characterized by increased

Acknowledgments and Disclosures

This work was supported by the National Institute of Mental Health Grant Nos. MH100047 (to RAB) and MH101221 (to EEE) and National Institute of Child Health and Human Development Grant No. U54 HD083091 to the University of Washington’s Center on Human Development and Disability. EEE is an investigator of the Howard Hughes Medical Institute.

Data were presented previously on two occasions: Data presented at 65th Annual Meeting for the American Academy of Child and Adolescent Psychiatry, October

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    JSB and CMH contributed equally to this work.

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