2. Academic Validation
  3. Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability

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.
Genay O Pilarowski 1 2,  Hilary J Vernon 2 3 4,  Carolyn D Applegate 2,  Leandros Boukas 1 2,  Megan T Cho 5,  Christina A Gurnett 6,  Paul J Benke 7,  Erin Beaver 8,  Jennifer M Heeley 8,  Livija Medne 9,  Ian D Krantz 9,  Meron Azage 10,  Dmitriy Niyazov 10,  Lindsay B Henderson 5,  Ingrid M Wentzensen 5,  Berivan Baskin 5,  Maria J Guillen Sacoto 5,  Gregory D Bowman 11 12,  Hans T Bjornsson 2 4 13
Affiliations

Affiliations

  • 1 Predoctoral Program in Human Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
  • 2 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
  • 3 Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland, USA.
  • 4 Department of Pediatrics, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
  • 5 GeneDx, Gaithersburg, Maryland, USA.
  • 6 Department of Neurology, Division of Pediatric Neurology, Washington University School of Medicine, Saint Louis, Missouri, USA.
  • 7 Joe DiMaggio Children's Hospital, Florida Atlantic School of Medicine, Hollywood, Florida, USA.
  • 8 Mercy Kids Genetics, Mercy Hospital, Saint Louis, Missouri, USA.
  • 9 Division of Human Genetics, Department of Pediatrics, Individualized Medical Genetics Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
  • 10 Department of Pediatrics, Ochsner Clinic, New Orleans, Louisiana, USA.
  • 11 T.C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, Maryland, USA.
  • 12 Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA.
  • 13 Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
PMID: 28866611 DOI: 10.1136/jmedgenet-2017-104759
Abstract

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.

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