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Homozygous CHD8 mutation intensifies ASD phenotypes and attenuates sex differences
Jinkyeong Kim1, Seungjoon Lee2, Eunkyu Hwang3
1Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
Molecular Psychiatry
|May 9, 2026
Summary
A homozygous CHD8 mutation intensifies autism spectrum disorder (ASD) traits and alters sex-specific patterns. This research reveals a new link between mutation strength and sexual dimorphism in ASD pathogenesis.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- CHD8 is a chromatin remodeler linked to autism spectrum disorders (ASD) and neurodevelopmental disorders.
- Heterozygous Chd8 mutations in mice often show mild ASD phenotypes, obscuring CHD8's precise role.
- Complete Chd8 knockout leads to embryonic lethality, necessitating alternative models.
Purpose of the Study:
- To investigate the impact of homozygous Chd8 mutations on ASD-related phenotypes.
- To explore the influence of genetic background and mutation strength on ASD traits and sexual dimorphism.
- To elucidate the molecular mechanisms underlying CHD8's role in neurodevelopment and ASD.
Main Methods:
- Generation of viable homozygous Chd8-mutant mice (Chd8N2373K/N2373K) with a human mutation on a hybrid genetic background.
- Comparative analysis of heterozygous (Chd8+/N2373K) and homozygous mutants across behavioral, physiological, and transcriptomic measures.
- Assessment of brain volume, cerebral blood flow, brain rhythms, synaptic transmission, and gene expression patterns.
Main Results:
- Homozygous Chd8 mutants exhibited more robust ASD-related behaviors, increased brain volume, and decreased cerebral blood flow and brain rhythms compared to heterozygotes.
- Sex-specific phenotypes were more pronounced in females in homozygous mutants on a hybrid background, unlike males in heterozygotes on a pure background.
- Gene dosage-dependent effects were observed, with homozygous mutations attenuating typical sex-specific severity patterns in a developmental and region-specific manner.
- Transcriptomic analysis identified altered pathways in synaptic function, RNA splicing, and mitochondrial activity.
Conclusions:
- Homozygous Chd8 mutations intensify ASD-related traits and reveal a novel gene dosage-dependent effect on sexual dimorphism in ASD.
- The genetic background interacts with mutation strength to modulate ASD phenotypes and sex-specific differences.
- These findings highlight the complex interplay between mutation severity, genetic background, and sex in neurodevelopmental disorders like ASD.
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01:43Sex-linked Disorders
Like autosomes, sex chromosomes contain a variety of genes necessary for normal body function. When a mutation in one of these genes results in biological deficits, the disorder is considered sex-linked.
01:35Pedigree Analysis
Overview
01:19X-linked Traits
In most mammalian species, females have two X sex chromosomes and males have an X and Y. As a result, mutations on the X chromosome in females may be masked by the presence of a normal allele on the second X. In contrast, a mutation on the X chromosome in males more often causes observable biological defects, as there is no normal X to compensate. Trait variations arising from mutations on the X chromosome are called “X-linked”.
01:19X-linked Traits
In most mammalian species, females have two X sex chromosomes and males have an X and Y. As a result, mutations on the X chromosome in females may be masked by the presence of a normal allele on the second X. In contrast, a mutation on the X chromosome in males more often causes observable biological defects, as there is no normal X to compensate. Trait variations arising from mutations on the X chromosome are called “X-linked”.
01:11Genetic Lingo
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02:50Dosage Compensation
In animals, gender is determined by the number and type of sex chromosome. For example, human females have two X chromosomes, and males have one X and one Y chromosome, whereas C.elegans with one X chromosome is a male, and the one with two X chromosomes is a hermaphrodite.
In addition to sexual development, the X chromosome has genes involved in autosomal functions such as brain development and the immune system. Therefore, males and females with distinct numbers of X chromosomes will have...
In addition to sexual development, the X chromosome has genes involved in autosomal functions such as brain development and the immune system. Therefore, males and females with distinct numbers of X chromosomes will have...