The clinical presentation caused by truncating CHD8 variants

Abstract

Variants in the chromodomain helicase DNA‐binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth and CHD8 is one of the causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (81%), ASDs (84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate‐to‐severe ID, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were non‐ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex‐dependent penetrance of CHD8 PTVs in humans.

A Novel Chd8 Mutant Mouse Displays Altered Ultrasonic Vocalizations and Enhanced Motor Coordination

“…In the current study, we report a new model created using a gene trap after Exon 31 of Chd8 that is predicted to result in a truncated protein product. This mutation is clinically relevant because multiple different truncating mutations in this region have been reported in the literature [Douzgou et al, 2019]. The current study adds to the growing resource of Chd8 mouse models.…”

A spontaneous missense mutation in the chromodomain helicase DNA‐binding protein 8 (CHD8) gene: a novel association with congenital myasthenic syndrome

“…Myasthenia has to date not been reported in association with CHD8 mutations. The clinical phenotype of patients with CHD8 mutations does vary, but macrosomia, macrocephalus, ASD [14,23,24] and gastrointestinal problems [25][26][27][28][29][30][31][32][33][34][35][36][37] appear to be constant features [29,38]. Some reports mention muscle hypotonia, however, in cases of microdeletions it often remains unclear, whether a certain symptom might be caused by CHD8 deficiency per se or by derangement of neighbouring genes [25].…”

“…Some reports mention muscle hypotonia, however, in cases of microdeletions it often remains unclear, whether a certain symptom might be caused by CHD8 deficiency per se or by derangement of neighbouring genes [25]. The majority of disease-associated variants are de novo microdeletions [25,33,38] and frameshift mutations [29,35,38]. So far, only one other missense mutation (p.R1797Q) and two deletions of one amino acid (p.K2287del; p.H2498del) have been published along with phenotype descriptions [29].…”

Insufficient Evidence for “Autism-Specific” Genes

“…Detailed phenotyping studies of individuals with pathogenic variants in specific genes are another source of data for evaluating ASD specificity. For example, the gene CHD8 is frequently discussed as a model "ASD gene" because mutations in this gene are associated with a high rate of ASD (Bernier et al, 2014 24 Twenty-one of the 25 (84%) had a diagnosis of ASD (Douzgou et al, 2019). 24 However, ascertainment bias is also a concern with clinical cohorts such as these, since individuals with mild phenotypes are less likely to be identified.…”

“…For example, the gene CHD8 is frequently discussed as a model "ASD gene" because mutations in this gene are associated with a high rate of ASD (Bernier et al, 2014 24 Twenty-one of the 25 (84%) had a diagnosis of ASD (Douzgou et al, 2019). 24 However, ascertainment bias is also a concern with clinical cohorts such as these, since individuals with mild phenotypes are less likely to be identified. For example, Guo et al (2018) assessed three families in which likely gene disrupting CHD8 mutations were transmitted from parents with full-scale IQ scores between 80 and 87 (verbal IQ 88-95, nonverbal IQ 75-79), establishing the possibility of relative sparing of cognition.…”