Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development

Abstract

Autism spectrum disorder (ASD) is a heterogeneous disease where efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in post-mitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…The oligo was cloned into the pT7 vector and guide RNAs was synthesized using the Mega transcript kit (Thermofisher) and purified as described. 33 To assess CRISPR efficiency, the targeted region was amplified by specific primers from total DNA as described 33 from 2 dpf F0 injected zebrafish embryos (F: 5 0 -TGCGAAATTATCCAATGCAG-3 0 ; R: 5 0 -CATTTTAAATTGA GCTCACACTCTTT-3 0 ). PCR products were denaturated and reannealed as follows: 95 C for 2 min, cooling progressively to 85 C (À2 C per second) and then 25 C (À0.1 C per second to 25 C) and finally 16 C. The PCR products were run on Criterion precast PAGE gels (Bio-Rad) to visualize homo-and heteroduplexes, indicative of small indels.…”

Chromodomain Helicase DNA-Binding Proteins in Stem Cells and Human Developmental Diseases

“…For CHD2, CHD6, and CHD7, mutations identified thus far are nonrecurrent (present in only individual cases), private mutations that account for a small fraction of ASD/ ID/epilepsy cases. In contrast to the rare isolated mutations in these three CHD genes, 13 different recurrent alleles of CHD8 have been observed in individuals with ASD/ID in association with macrocephaly and gastrointestinal disturbance [66,70,[75][76][77][78]. In cultured cells, CHD8 has been shown to bind CHD7 and to both bind and regulate p53 and inhibit its proapoptotic effects during development; thus, it is surprising that loss of CHD8 is not associated with broader phenotypic effects in humans [79][80][81][82].…”

Environmental Influences on Biochemistry in Autism Spectrum Disorder

“…Although the numerous genetic studies conducted on ASD have been successful in identifying potential chromosomal abnormalities, truncations and missense mutations, the detection of the specific genetic variants responsible for ASD have been mostly elusive, likely due to the high genetic complexity and probable heterogeneity of the disorder [8]. Notably, a recent study provided the first clear link to a subtype of autism and a specific genetic mutation in the CHD8 gene [20], indicating that more progress may follow in the genetic understanding of other subtypes of ASD.…”