# Modeling genetic contributions to phenotype variation and neurodevelopmental disorder susceptibility

> **NIH NIH R21** · CHILDREN'S HOSPITAL OF LOS ANGELES · 2020 · $211,875

## Abstract

Human genetic studies have identified a small number of high confidence causal genes for autism spectrum
disorder (ASD). Even for these highly penetrant mutations, there are individual differences in ASD-relevant
symptoms and other co-occurring behavioral and medical phenotypes [e.g. anxiety, cognitive deficits,
gastrointestinal (GI) disturbances]. Symptom heterogeneity diminishes the ability to predict response to
treatments, but presently there is limited understanding of how genomic risk variants, genetic background and
environmental factors impact ASD risk and clinical heterogeneity. Animal genetic reference panels provide
opportunities to systemically study genetic risk variants in relation to a panel of diverse, deep sequenced and
reproducible recombinant inbred (RI) genetic backgrounds. This strategy is highly relevant to discovery of
human disease etiology, currently applied mostly to experimental models of non-brain disorders, including
susceptibility (and reduced vulnerability) to infectious diseases, toxins, cancer, and respiratory, GI and
metabolic disorders. Here, we propose to use this strategy to address the knowledge gaps in understanding
ASD susceptibility and phenotype heterogeneity. As background, chromodomain helicase DNA binding protein
8 (CHD8) encodes a chromatin remodeling protein that is a very high confidence ASD-risk gene, accounting
for ~0.5% of cases. Macrocephaly and ASD are expressed in nearly all subjects with CHD8 mutations, but
symptoms can vary in levels of impairment and even expression. In mice, homozygous null mutations in Chd8
are embryonic lethal. Heterozygous null mice (Chd8+/-) recapitulate macrocephaly, but exhibit varying degrees
of emotional dysregulation, repetitive behavior, social communication and learning deficits, all of which has
been done on a single background (C57BL/6) strain. The proposed experiments leverage the phenotypic
features associated with CHD8 haploinsufficiency in humans and mice with our laboratory’s recent studies
showing that RI mouse strains express broad heterogeneity and high heritability of social and cognitive traits.
Proposed experiments will examine how strain genetic diversity imposes susceptibility (or reduced
vulnerability) to the expression of social, cognitive and emotional phenotypes, as well as macrocephaly and GI
disturbances, in Chd8+/- mice. Using the Collaborative Cross (CC), a highly genetically diverse and fully
sequenced RI mouse panel, the studies provide an exciting opportunity to reveal the effects of genetic diversity
on ASD-relevant phenotypes. Aim 1 will determine the impact of genetic background on behavioral and
physiological phenotypes in a newly generated CC/WT and CC/Chd8+/- mouse panel. Aim 2 will apply RNA-
sequencing in frontal cortex and dorsal hippocampus to identify gene networks that underlie social and
cognitive deficits in the most susceptible CC/Chd8+/- strains. This work advances the power of preclinical
experimental studies, whole-gen...

## Key facts

- **NIH application ID:** 9944682
- **Project number:** 5R21MH118685-02
- **Recipient organization:** CHILDREN'S HOSPITAL OF LOS ANGELES
- **Principal Investigator:** PAT LEVITT
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $211,875
- **Award type:** 5
- **Project period:** 2019-06-05 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944682

## Citation

> US National Institutes of Health, RePORTER application 9944682, Modeling genetic contributions to phenotype variation and neurodevelopmental disorder susceptibility (5R21MH118685-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9944682. Licensed CC0.

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