CHD8 – Intellectual Developmental Disorder with Autism and Macrocephaly

Chromodomain helicase DNA-binding protein 8 (CHD8) is an ATP-dependent chromatin remodeler essential for neurodevelopment. Heterozygous, often de novo, loss-of-function variants in CHD8 cause intellectual developmental disorder with autism and macrocephaly (IDDAM) (Intellectual developmental disorder with autism and macrocephaly). Clinical features include global developmental delay, macrocephaly, autism spectrum disorder, hypotonia, gastrointestinal dysmotility and distinctive facial features.

In the largest cohort to date, 106 individuals with IDDAM were studied, including 36 newly described cases, revealing 29 unique nonsense, 25 frameshift, 24 missense and 12 splice site variants, plus two in-frame deletions, one multi-exon deletion and one translocation in CHD8 (106 probands) (PMID:36182950). Methylation analysis in 13 patients demonstrated the characteristic CHD8 episignature in 11 (85%). Variants arose de novo in all cases, consistent with autosomal dominant inheritance.

Phenotypic analysis showed intellectual disability in 68% and hypotonia in 29% of patients, while behavioral abnormalities occurred in 88%, including autism spectrum features (76%), short attention span (32%), abnormal social behaviour (31%), sleep disturbance (29%) and impaired social interactions (28%) (PMID:36182950). Systemic findings included musculoskeletal (79%), digestive (53%) and genitourinary (18%) involvement. Severity did not differ by sex but missense variant carriers showed milder features.

Functional studies across multiple models confirm CHD8 haploinsufficiency as the mechanism of disease. Chd8+/− mice display macrocephaly, disrupted neurogenesis, delayed cortical development and ASD-like behaviors, including altered social interaction and repetitive behaviors (PMID:27602517). Knockdown in human neural progenitors shortens G1 phase, elevates cyclin E and ERK phosphorylation, and favors progenitor proliferation, providing a cellular basis for macrocephaly (PMID:27694995).

No conflicting evidence has disputed the CHD8–IDDAM association. Integration of extensive clinical, genetic and experimental data firmly establishes CHD8 haploinsufficiency as the cause of IDDAM, with strong genotype–phenotype correlations and conserved molecular pathology.

Key Take-home: CHD8 heterozygous loss-of-function variants cause an autosomal dominant syndrome of intellectual disability, autism and macrocephaly; genetic testing and functional methylation assays are indicated for accurate diagnosis and counselling.

References

• American Journal of Human Genetics • 2022 • A cohort of 106 individuals with CHD8-related intellectual developmental disorder with autism and macrocephaly (IDDAM): genotype–phenotype analysis PMID:36182950
• Nature • 2016 • CHD8 haploinsufficiency results in autistic-like phenotypes in mice. PMID:27602517
• Nature Neuroscience • 2016 • Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling. PMID:27694995

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