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

Publication ,  Journal Article
Pilarowski, GO; Vernon, HJ; Applegate, CD; Boukas, L; Cho, MT; Gurnett, CA; Benke, PJ; Beaver, E; Heeley, JM; Medne, L; Krantz, ID; Azage, M ...
Published in: J Med Genet
August 2018

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.

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Published In

J Med Genet

DOI

EISSN

1468-6244

Publication Date

August 2018

Volume

55

Issue

8

Start / End Page

561 / 566

Location

England

Related Subject Headings

  • Structure-Activity Relationship
  • Protein Conformation
  • Phenotype
  • Mutation, Missense
  • Models, Molecular
  • Infant
  • Humans
  • Histones
  • Genetics & Heredity
  • Genetic Predisposition to Disease
 

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Pilarowski, G. O., Vernon, H. J., Applegate, C. D., Boukas, L., Cho, M. T., Gurnett, C. A., … Bjornsson, H. T. (2018). Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability. J Med Genet, 55(8), 561–566. https://doi.org/10.1136/jmedgenet-2017-104759
Pilarowski, Genay O., Hilary J. Vernon, Carolyn D. Applegate, Leandros Boukas, Megan T. Cho, Christina A. Gurnett, Paul J. Benke, et al. “Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.J Med Genet 55, no. 8 (August 2018): 561–66. https://doi.org/10.1136/jmedgenet-2017-104759.
Pilarowski GO, Vernon HJ, Applegate CD, Boukas L, Cho MT, Gurnett CA, et al. Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability. J Med Genet. 2018 Aug;55(8):561–6.
Pilarowski, Genay O., et al. “Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability.J Med Genet, vol. 55, no. 8, Aug. 2018, pp. 561–66. Pubmed, doi:10.1136/jmedgenet-2017-104759.
Pilarowski GO, Vernon HJ, Applegate CD, Boukas L, Cho MT, Gurnett CA, Benke PJ, Beaver E, Heeley JM, Medne L, Krantz ID, Azage M, Niyazov D, Henderson LB, Wentzensen IM, Baskin B, Sacoto MJG, Bowman GD, Bjornsson HT. Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability. J Med Genet. 2018 Aug;55(8):561–566.

Published In

J Med Genet

DOI

EISSN

1468-6244

Publication Date

August 2018

Volume

55

Issue

8

Start / End Page

561 / 566

Location

England

Related Subject Headings

  • Structure-Activity Relationship
  • Protein Conformation
  • Phenotype
  • Mutation, Missense
  • Models, Molecular
  • Infant
  • Humans
  • Histones
  • Genetics & Heredity
  • Genetic Predisposition to Disease