Objective:

To describe the movement disorder phenomenology in a 5-year-old female with a novel CHD8 missense variant compared to literature review.

Background:

CHD8 gene encodes a Chromodomain-Helicase-DNA binding protein crucial for brain development and regulation of gene expression. Heterozygous CHD8 variants are associated with intellectual developmental disorder with autism (ASD) and macrocephaly (IDDAM).

Design/Methods:

Medical history was collected through parental report, medical records review and video recording of the neurological exam. Magnetic resonance imaging (MRI) of the neuro axis, chromosomal microarray analysis (CMA), and autism genetic panel were completed. Literature review was performed.

Results:

The proband is a 5-year-old female born at 32 weeks with hypotonia, macrocephaly and facial dysmorphia. Early course was notable for developmental delays, generalized tonic-clonic seizures and ASD at age 2 years; impaired gait, torticollis and fine motor difficulties at age 3 years; bi-brachial jerky and athetoid dystonia at age 5 years. MRI of the neuro axis was normal. Genetic testing identified two novel, biallelic, rare (MAF < 0.01), missense variants of uncertain significance (VUS) in the CHD8 gene: c.5645G>C p.(Arg1882Thr) predicted pathogenic by in silico tools, and c.5935C>T; p.(Arg1979Cys) predicted benign by most in silico tools. Parents did not report neurological symptoms. Another VUS was reported in the BCL11A gene (c.1568G>A p.(Arg523His)) inherited from the father.

Conclusions:

Dystonia has been reported in 6 cases with heterozygous, CHD8 loss-of-function variants, while missense variants previously have been associated with ASD but not movement disorder. This patient has a novel CHD8 missense variant with both ASD and dystonia. The biallelic effect of CHD8 variants and digenic contribution of BCL11A cannot be definitively determined with the available data. Interestingly, CHD8 penetrance seems to be higher in males for ASD and in females for dystonia. This case may shed new light on CHD8-associated phenotype.