Background CHD8 is one of a few genes in which de novo loss of function mutations have been identified in multiple cases across multiple autism cohorts in recent extensive exome sequencing studies. CHD8 is an ATP-dependent chromodomain helicase involved in chromatin remodelling and regulation of Wnt/beta-catenin and p53 pathways, which are pathways that have been implicated in non-syndromic and syndromic autism and intellectual disability.
Objectives We will describe a patient with autism and intellectual disability with a novel CHD8 mutation. We also review the phenotype of previously reported patients with CHD8 loss of function mutations.
Methods Exome sequencing of the proband and parents was used to identify de novo variants using the trio approach. A PubMed-based literature search identified other reported patients.
Results Our patient has a de novo truncating CHD8 mutation (c.4342C >T, NM_020920). He is macrocephalic (>+3SD), and has extremely tall stature with proportionate weight (>+7SD), suggestive of an overgrowth phenotype. Other patients with CHD8 mutations that have been reported in the literature also have macrocephaly and a tendency to taller stature.
Conclusions CHD8 mutations may cause syndromic autism. Further delineation of this phenotype will be helpful for diagnostic and prognostic guidance in the future. The association of a truncating CHD8 mutation with macrocephaly and overgrowth is particularly interesting since other disorders of chromatin remodelling implicated in the Wnt/beta-catenin pathway, such as Coffin-Siris and Weaver syndromes, also have abnormal neurodevelopment associated with altered head size and in some instances generalised overgrowth.
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