ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000014.8) (NC_000014.9)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23160955 O'Roak et al. 2012 described nine de novo mutations in the CHD8 gene amongst 2,446 probands with autism spectrum disorder (ASD), where two cases were previously reported (patient# 13844.p1 and 12752.p1 in PMID: 22495309). The nine mutations included three nonsense (p.Ser62X, p.Gln1238X and p.Arg1337X), four frameshift (p.Tyr747X, p.Gln2103ArgfsX3, p.Leu2120ProfsX13 and p.Asn2371LysfsX2), one amino acid deletion (p.His2498del) and one intronic canonical splice site disruption (c.3519-2A>G).
24998929 Bernier et al. (2014) reported twelve de novo truncating mutations in 3,730 children with developmental delay or ASD, where nine cases were previously reported by O'Roak et al. (2012). Apart from a diagnosis of ASD, the common features amongst reported patients included macrocephaly, prominent forehead, wide-set eyes, pointed chin as well as an increased rates of gastrointestinal (GI) complaints and marked sleep dysfunction. The three de novo mutations exclusively identified in this paper included one nonsense (p.Glu1114X) and two frameshift (p.Glu1932SerfsX3 and p.Glu2136ArgfsX6) mutations. Apart from the de novo mutations listed above, other reported cases included one frameshift mutation (p.Val984X) found to be maternally inherited, three missense mutations (p.Arg910Gln - unknown inheritance, p.Gly1710Val - maternally inherited, and p.Arg1797Gln - paternally inherited with similar phenotype), one case with 5-kp duplication found to be paternally inherited, and two cases with duplication of unknown inheritance. Functional studies with Chd8 knockdown in zebrafish recapitulates an overgrowth of the head (10-15% enlargement) and GI problems.
27824329 Wang et al. (2016) studied 1,543 Chinese ASD probands and reported two de novo truncating mutations (p.Lys750Asnfs*14 and p.Arg1897Thrfs*23). The common phenotype included ASD, intellectual disability, developmental delay (motor and speech), repetitive behaviour, macrocephaly, attention problems, tall and overweight.

Haploinsufficiency phenotype comments:

Other papers with de novo mutations found in CHD8 gene included: [1]. McCarthy et al. (2014) reported a nonsense mutation (p.52173X) in a patient with ASD and schizophrenia (PMID: 24776741); [2]. Lee et al. (2014) described patient 97 (p.Arg773X) and patient 115 (p.Arg582X), where the common features included autism (PMID: 25326637); [3]. De Rubeis et al. (2014) reported two autistic patients with frameshift mutation (p.S1606RfsX8 and p.Y1642LfsX25) (PMID: 25363760). Functional studies by Suetterlin et al. (2018) (PMID: 29668850) showed that the CHD8 protein levels were reduced by 51% in E12.5 neocortices of Chd8+/- mice validating CHD8 haploinsufficiency. There was no evidence of truncated protein products, which supported the nonsense-mediated decay event. Furthermore, the Chd8+/- mice showed a wider interorbital distance (i.e. hypertelomeric phenotype), an increase in the anterior-posterior length of the interparietal bone (i.e. craniofacial anomalies) and an increase of 2.7% in total brain volume. Evidence for delayed in motor development and hyperactivity was observed in the Chd8+/- pups, whilst adult Chd8+/- exhibited hypoactive phenotype. Notably, two independent experimental approaches at different time points identified specific axon guidance and cell adhesion genes that might be relevant in functional connectivity phenotype. Finally, the author concluded that the 'abnormalities in specific cortical-hippocampal circuits involved in sensory processing may underlie some of the unique anomalous behaviours observed in Chd8+/- mice, and by extension, the neuropsychiatric symptoms in patients with CHD8 haploinsufficiency'. Another functional study by Gompers et al. (2017) (PMID: 28671691) showed that Chd8+/del5 mice with germline 5-bp and 14-bp deletion mutations in exon 5 of the CHD8 gene resulted in its loss-of-function. Overall, there was a link to cognitive deficits, increased regional brain volume and disruptions of the neurodevelopment biological pathways.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity