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

American Journal of Medical Genetics. Part a
Nancy MernerCarl Ernst

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 supp...Continue Reading

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Citations

Mar 7, 2017·Nature Reviews. Genetics·Jacob A S VorstmanJoachim F Hallmayer
Dec 17, 2016·Journal of Neurodevelopmental Disorders·Vickie KwanKarun K Singh
Nov 14, 2019·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Philip J OstrowskiKatrina Tatton-Brown
Nov 20, 2019·Autism Research : Official Journal of the International Society for Autism Research·Weicheng DuanBo Xiong
Aug 21, 2020·Autism Research : Official Journal of the International Society for Autism Research·Samuel W HulbertYong-Hui Jiang
Apr 20, 2019·Clinical Genetics·Sofia DouzgouSiddharth Banka
Dec 12, 2019·Neurogenetics·Thomas SmolJamal Ghoumid
Dec 13, 2019·American Journal of Medical Genetics. Part C, Seminars in Medical Genetics·Cheryl CytrynbaumRosanna Weksberg
Apr 23, 2020·Nature Reviews. Genetics·Christian P SchaafJacob A S Vorstman
Jun 12, 2018·International Journal of Genomics·Chuphong ThongnakChonlaphat Sukasem
Jan 23, 2021·Journal of Clinical Medicine·Anke Hoffmann, Dietmar Spengler
Dec 23, 2020·American Journal of Human Genetics·Brooke SadlerGabe Haller
Apr 14, 2017·Cell Reports·Randall J PlattFeng Zhang
May 9, 2021·Neurochemistry International·Leora D'SouzaBhavana Muralidharan

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