CHD8 was first reported in relation to autosomal dominant autism spectrum disorder in 2012 (O'Roak et al., PMID: 22495309). In addition to an increased likelihood of a diagnosis of autism spectrum disorder, individuals with pathogenic variants in CHD8 have variable degrees of intellectual disability, an overgrowth phenotype with macrocephaly and increased height, and dysmorphic facial features (PMID: 24998929). We therefore decided to curate for the generic term complex neurodevelopmental disorder.
Eight truncating variants (frameshift, nonsense) that have been reported in 8 probands in 4 publications (PMIDs: 22495309, 24998929, 26789910, 27824329) are included in this curation. Most variants are de novo; one individual inherited a CHD8 variant from a heterozygous mother who has some autistic features but has not been clinically diagnosed. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by a zebrafish model and a mouse model.
In summary, there is definitive evidence supporting the relationship between CHD8 and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 16, 2018 (SOP Version 5).
The CHD8 gene was first reported in relation to autosomal dominant autism spectrum disorder in 2012 (O'Roak et al., PMID: 22495309). At least 8 truncating variants have been reported in 4 publications (PMIDs: 22495309, 24998929, 26789910, 27824329). Most variants are de novo; one individual inherited a CHD8 variant from a heterozygous mother who has some autistic features but has not been clinically diagnosed. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. In addition to an increased likelihood of a diagnosis of autism spectrum disorder, individuals with pathogenic variants in CHD8 have variable degrees of intellectual disability, an overgrowth phenotype with macrocephaly and increased height, and dysmorphic facial features (PMID: 24998929). We therefore decided to curate for the generic term complex neurodevelopmental disorder. This gene-disease association is supported by a zebrafish model and a mouse model. In summary, CHD8 is definitively associated with autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 7/16/2018.
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