A de novo frameshift mutation in chromodomain helicase DNA-binding domain 8 (CHD8): A case report and literature review

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), schizop...

Full description

Saved in:
Bibliographic Details
Published in:American journal of medical genetics. Part A 2016-05, Vol.170A (5), p.1225-1235
Main Authors: Merner, Nancy, Forgeot d'Arc, Baudouin, Bell, Scott C., Maussion, Gilles, Peng, Huashan, Gauthier, Julie, Crapper, Liam, Hamdan, Fadi F., Michaud, Jacques L., Mottron, Laurent, Rouleau, Guy A., Ernst, Carl
Format: Article
Language:English
Subjects:
Adolescent
autism
Autism Spectrum Disorder - genetics
Autism Spectrum Disorder - physiopathology
CHD8
Child
Child, Preschool
Comparative Genomic Hybridization
DNA-Binding Proteins - genetics
Exons - genetics
Female
Frameshift Mutation
Gene Expression Regulation, Developmental
Genotype
Humans
Male
neurodevelopment
schizophrenia
Schizophrenia - genetics
Schizophrenia - physiopathology
Transcription Factors - genetics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. © 2016 Wiley Periodicals, Inc.
ISSN:1552-4825
1552-4833
DOI:10.1002/ajmg.a.37566