Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability

J Med Genet. 2018 Aug;55(8):561-566. doi: 10.1136/jmedgenet-2017-104759. Epub 2017 Sep 2.


Background: The list of Mendelian disorders of the epigenetic machinery has expanded rapidly during the last 5 years. A few missense variants in the chromatin remodeler CHD1 have been found in several large-scale sequencing efforts focused on uncovering the genetic aetiology of autism.

Objectives: To explore whether variants in CHD1 are associated with a human phenotype.

Methods: We used GeneMatcher to identify other physicians caring for patients with variants in CHD1. We also explored the epigenetic consequences of one of these variants in cultured fibroblasts.

Results: Here we describe six CHD1 heterozygous missense variants in a cohort of patients with autism, speech apraxia, developmental delay and facial dysmorphic features. Importantly, three of these variants occurred de novo. We also report on a subject with a de novo deletion covering a large fraction of the CHD1 gene without any obvious neurological phenotype. Finally, we demonstrate increased levels of the closed chromatin modification H3K27me3 in fibroblasts from a subject carrying a de novo variant in CHD1.

Conclusions: Our results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.

Keywords: chromatin; epigenetic machinery; human disease; neurological dysfunction; speech apraxia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Child
  • Child, Preschool
  • Chromatin Assembly and Disassembly / genetics*
  • DNA Helicases / chemistry
  • DNA Helicases / genetics*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • Developmental Disabilities / diagnosis
  • Developmental Disabilities / genetics*
  • Facies
  • Female
  • Fibroblasts / metabolism
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Histones / metabolism
  • Humans
  • Infant
  • Models, Molecular
  • Mutation, Missense*
  • Phenotype
  • Protein Conformation
  • Structure-Activity Relationship


  • DNA-Binding Proteins
  • Histones
  • DNA Helicases
  • CHD1 protein, human