CHD8 – CHD8-related Intellectual Disability

Chromodomain helicase DNA‐binding protein 8 (CHD8) encodes an ATP‐dependent chromatin remodeler essential for neurodevelopment. Heterozygous loss‐of‐function variants in CHD8 are associated with intellectual disability characterized by macrocephaly, overgrowth, and variable neurodevelopmental features. Three cohorts have described CHD8 protein‐truncating variants in 16, 25, and 27 unrelated individuals, respectively (PMID:26789910; PMID:31001818; PMID:31721432). Most variants arise de novo, supporting an autosomal dominant inheritance mechanism with haploinsufficiency as the likely pathogenic mechanism.

While segregation data are limited, one CHD8 variant was inherited from an affected parent, indicating potential familial transmission (PMID:30631761). The variant spectrum encompasses over 30 protein‐truncating alleles including nonsense, frameshift, and splice‐site mutations as well as pathogenic missense changes. A recurrent truncating variant, c.3724C>T (p.Arg1242Ter), has been reported in multiple unrelated probands, underscoring a mutational hotspot.

Functional studies in human induced pluripotent stem cell‐derived neural progenitors and cerebral organoids demonstrate that CHD8 haploinsufficiency disrupts cell cycle regulation, Wnt/β‐catenin signaling, and neurogenic gene programs, leading to altered proliferation and differentiation (PMID:27694995). Transcriptomic profiling reveals dysregulation of thousands of genes, including those implicated in head size and ASD risk, providing mechanistic insight into the macrocephaly phenotype.

Mouse models heterozygous for Chd8 mutations recapitulate core neurodevelopmental phenotypes, showing delayed cortical neurogenesis, increased brain volume, and autism‐like behaviors; restoration of Wnt signaling rescues transcriptional and behavioral deficits (PMID:27602517). These in vivo data confirm the crucial role of CHD8 dosage in brain development and function.

In summary, extensive genetic and experimental evidence establishes CHD8 haploinsufficiency as a strong cause of intellectual disability with macrocephaly. CHD8 should be included in diagnostic gene panels for neurodevelopmental disorders, guiding clinical assessment and management.

References

• American Journal of Medical Genetics Part A • 2016 • A de novo frameshift mutation in chromodomain helicase DNA-binding domain 8 (CHD8): A case report and literature review. PMID:26789910
• Clinical Genetics • 2019 • The clinical presentation caused by truncating CHD8 variants. PMID:31001818
• American Journal of Medical Genetics Part C • 2019 • The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients. PMID:31721432
• Nature Neuroscience • 2016 • Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling. PMID:27694995
• Nature • 2016 • CHD8 haploinsufficiency results in autistic-like phenotypes in mice. PMID:27602517

Evidence Based Scoring (AI generated)