ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.