High-throughput precision gene editing and multi-omics profiling of patient-specific CHD8 variants in human-derived stem cells and induced neurons

  • Awarded: 2022
  • Award Type: Targeted: Genomics of ASD: Pathways to Genetic Therapies
  • Award #: 1010692

The tremendous genotypic and phenotypic diversity underlying autism spectrum disorder (ASD) has made it extremely challenging to pinpoint causal mechanisms, distinguish the effects of individual genetic variants, stratify patients into subtypes and develop treatments. High-throughput methods enabling the systematic characterization of many ASD genes and variants across development, cell types, spatial location and in response to interventions will lead to major advances in our understanding of the condition and capacity to improve the lives of individuals and their families.

Randall Platt and his team’s overarching goal is to combine the CRISPR-based precision gene editing technologies with single-cell RNA sequencing and chromatin accessibility profiling to systematically engineer and functionally dissect the function of hundreds of patient-specific variants in ASD risk genes. For proof-of-concept, Platt and his team plan to focus on the high-confidence ASD risk gene CHD8.

Platt and others have previously demonstrated that in mice and human neurons differentiated from stem cells, heterozygous loss-of-function mutations in CHD8 lead to broad transcriptional changes enriched in ASD-related genes and pathways as well as disruption of chromatin organization, synaptic physiology and animal behavior1-4. Other investigators have also linked CHD8 to cancer. More than 500 mutations in CHD8 have been identified in individuals, but it remains unknown how they differentially affect cellular phenotypes and explain clinical heterogeneity.

This study aims to interrogate the impact of each patient-specific variant in CHD8 on a range of phenotypes in human stem cells and induced neurons derived from these cells. Findings may help stratify pathogenic from non-pathogenic CHD8 variants, explain how mutations in the same gene may increase susceptibility to ASD versus other CHD8-linked conditions, prioritize distinct convergent/divergent mechanisms for follow-up studies and highlight entry points for therapeutic interventions. The methods and concepts developed here may also be readily applicable to any ASD risk gene of interest, fueling progress towards a better understanding of the condition.


  1. Katayama Y. et al. Nature 537, 675-679 (2016) PubMed
  2. Platt R. et al. Cell Rep. 19, 335-350 (2017) PubMed
  3. Gompers A. L. et al. Nat. Neurosci. 20, 1062-1073 (2022) PubMed
  4. Shi X. et al. Am. J. Hum. Genet. 110, 1750-1768 (2023) PubMed
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