CHD8 – Autism Spectrum Disorder

CHD8 (Chromodomain helicase DNA-binding protein 8) is robustly implicated in autism spectrum disorder (ASD). CHD8 loss-of-function alleles were first flagged by balanced chromosomal abnormalities in autism cases (PMID:22521361). Large-scale exome sequencing in 42,607 ASD probands confirmed CHD8 as one of the most recurrent de novo risk genes, reaching exome-wide significance (PMID:35982159).

This gene-disease relationship meets ClinGen Definitive criteria. Over 27 unrelated individuals harbor de novo null CHD8 variants in independent cohorts (PMID:31721432), with concordant in vitro and in vivo functional data demonstrating neurodevelopmental impact.

Inheritance is autosomal dominant, driven by heterozygous de novo mutations. Segregation beyond sporadic cases is limited (0 additional segregating relatives), reflecting high penetrance and de novo origin.

The variant spectrum is dominated by protein-truncating mutations with occasional missense changes. For example, c.3725G>T (p.Arg1242Leu) disrupts the conserved helicase domain and impairs axon development and neuronal migration in cortical neurons (PMID:30574290).

Functional studies across cellular and animal models demonstrate that CHD8 haploinsufficiency dysregulates cell-cycle genes, shortens G1 phase, perturbs Wnt/β-catenin signaling, and leads to impaired neuronal migration and axonal growth—hallmarks of ASD pathophysiology (PMID:27694995; PMID:30574290).

Integration of genetic and experimental evidence supports a haploinsufficiency mechanism for CHD8 in ASD. Clinical sequencing of CHD8 informs diagnosis in individuals with autism, macrocephaly, and comorbid neurodevelopmental features. Model systems and rescue assays provide avenues for therapeutic development.

Key take-home: CHD8 haploinsufficiency constitutes a definitive cause of autism spectrum disorder with direct applications in molecular diagnosis and mechanistic research.

References

• Cell • 2012 • Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. PMID:22521361
• American journal of medical genetics. Part C, Seminars in medical genetics • 2019 • The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients. PMID:31721432
• Molecular autism • 2018 • Autism-associated CHD8 deficiency impairs axon development and migration of cortical neurons. PMID:30574290
• Nature genetics • 2022 • Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes. PMID:35982159
• Nature neuroscience • 2016 • Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling. PMID:27694995

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