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

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

Author information

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.

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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