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
  • 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.