MG-126 A de novo truncating mutation in the chromatin remodeler chd8 in a patient with autism, macrocephaly and overgrowth. (4th December 2015)

• Record Type: Journal Article
• Authors: Au, PY Billie; Smith, Christopher S; Lamont, Ryan E; Racher, Hilary E; Parboosingh, Jillian S; Bernier, Francois; Innes, A Micheil
• Is Part Of: Journal of medical genetics. Volume 52(2015)Supplement 1
• Page Start: A6
• Page End: A7
• Publication Date: 2015-12-04
• Subjects: Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2015-103577.17
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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.