title: A de novo frameshift mutation in chromodomain helicase DNA-binding domain 8 (CHD8): A case report and literature review.
abstract: Mutations in chromodomain helicase DNA-binding domain 8 (CHD8) have been identified in independent genotyping studies of autism spectrum disorder. To better understand the phenotype associated with CHD8 mutations, we genotyped all CHD8 exons in carefully assessed cohorts of autism (n = 142), schizophrenia (SCZ; n = 143), and intellectual disability (ID; n = 94). We identified one frameshift mutation, seven non-synonymous variants, and six synonymous variants. The frameshift mutation, p.Asn2092Lysfs*2, which creates a premature stop codon leading to the loss of 212 amino acids of the protein, was from an autism case on whom we present multiple clinical assessments and pharmacological treatments spanning more than 10 years. RNA and protein analysis support a model where the transcript generated from the mutant allele results in haploinsufficiency of CHD8. This case report supports the association of CHD8 mutations with classical autism, macrocephaly, infantile hypotonia, speech delay, lack of major ID, and psychopathology in late adolescence caused by insufficient dosage of CHD8. Review of 16 other CHD8 mutation cases suggests that clinical features and their severity vary considerably across individuals; however, these data support a CHD8 mutation syndrome, further highlighting the importance of genomic medicine to guide clinical assessment and treatment.
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|Montreal Neurological Institute, Montreal, Quebec, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Merner
authors.affiliation: Riviere-des-Prairies Hospital, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Baudouin
authors.initials: B
authors.lastname: Forgeot d'Arc
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Douglas Hospital Research Institute, Montreal, Quebec, Canada.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Bell
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Douglas Hospital Research Institute, Montreal, Quebec, Canada.
authors.forename: Gilles
authors.initials: G
authors.lastname: Maussion
authors.affiliation: Douglas Hospital Research Institute, Montreal, Quebec, Canada.
authors.forename: Huashan
authors.initials: H
authors.lastname: Peng
authors.affiliation: CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Gauthier
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: Liam
authors.initials: L
authors.lastname: Crapper
authors.affiliation: CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Fadi F
authors.initials: FF
authors.lastname: Hamdan
authors.affiliation: CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.affiliation: Riviere-des-Prairies Hospital, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Mottron
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|Montreal Neurological Institute, Montreal, Quebec, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.|Department of Human Genetics, McGill University, Montreal, Quebec, Canada.|Douglas Hospital Research Institute, Montreal, Quebec, Canada.|Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Ernst
mesh_terms: D000293:Adolescent; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006801:Humans; D008297:Male; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C523331:CHD8 protein, human; D004268:DNA-Binding Proteins; D014157:Transcription Factors
keywords: CHD8; autism; neurodevelopment; schizophrenia